Novel succinate salt of O-desmethyl-venlafaxine

ABSTRACT

A novel salt of O-desmethyl venlafaxine is provided, O-desmethylvenlafaxine succinate. Pharmaceutical compositions, dosage forms and methods of use are also provided.

[0001] This application claims priority from copending provisionalapplication(s) serial No. 60/268,214 filed on Feb. 12, 2001 and60/297,963 filed on Jun. 13, 2001.

FIELD OF THE INVENTION

[0002] The present invention provides a novel salt ofO-desmethyl-venlafaxine, O-desmethyl-venlafaxine succinate, as well aspolymorphs, pharmaceutical compositions, dosage forms, and methods ofuse with the same.

BACKGROUND OF THE INVENTION

[0003] O-desmethyl venlafaxine is a major metabolite of venlafaxine andhas been shown to inhibit norepinephrine and serotonin uptake. Klamerus,K. J. et al., “Introduction of the Composite Parameter to thePharmacokinetics of Venlafaxine and its Active O-Desmethyl Metabolite”,J. Clin. Pharmacol. 32:716-724 (1992). O-desmethyl-venlafaxine,chemically named 1-[2-(dimethylamino)-1-(4-phenol)ethyl]-cyclohexanol,was exemplified as a fumarate salt in U.S. Pat. No. 4,535,186. However,the fumarate salt of O-desmethyl-venlafaxine has unsuitablephysicochemical and permeability characteristics.O-desmethyl-venlafaxine is also exemplified as a free base inInternational Patent Publication No. WO 00/32555.

[0004] Salt formation provides a means of altering the physicochemicaland resultant biological characteristics of a drug without modifying itschemical structure. A salt form can have a dramatic influence on theproperties of the drug. The selection of a suitable salt is partiallydictated by yield, rate and quantity of the crystalline structure. Inaddition, hygroscopicity, stability, solubility and the process profileof the salt form are important considerations. The identification of asalt form that exhibits a suitable combination of properties can bedifficult.

[0005] Solubility is one important characteristic of a salt form thatcan affect its suitability for use as a drug. Where aqueous solubilityis low, i.e. less than 10 mg/ml, the dissolution rate at in vivoadministration can be rate limiting in the absorption process leading topoor bioavailability. Hygroscopicity is also an importantcharacteristic. Compounds having low hygroscopicity tend to have betterstability and easier processing.

SUMMARY OF THE INVENTION

[0006] The present invention provides a novel salt ofO-desmethyl-venlafaxine, O-desmethyl-venlafaxine succinate (hereinafterreferred to as “ODV succinate”). The novel salt of the present inventionhas properties which are particularly suitable for use as a drug,including improved solubility, permeability, and bioavailability. Forexample, ODV succinate is well absorbed in the gastrointestinal tract.Furthermore, oral administration of ODV succinate results in a lowerincidence of nauseau, vomiting, diarrhea, abdominal pain, headache,vaso-vagal malaise, and/or trismus than oral administration ofvenlafaxine, O-desmethyl-venlafaxine, and salts ofO-desmethyl-venlafaxine other than ODV succinate. Additionally,sustained release oral formulations of ODV succinate result in a lowerincidence of nauseau, vomiting, diarrhea, abdominal pain, headache,vaso-vagal malaise, and/or trismus than oral administration ofvenlafaxine, O-desmethyl-venlafaxine, and salts ofO-desmethyl-venlafaxine (other than sustained release oral formulationsof ODV succinate). Pharmaceutical compositions comprising ODV succinateand pharmaceutically acceptable carriers or excipients are alsoprovided. Preferably, the pharmaceutical compositions comprise an amountof ODV succinate effective to treat the desired indication in an animal,such as a human.

[0007] In further embodiments of the present invention are providedmethods of treating patients suffering from depression (include, but notlimited to, major depressive disorder, bipolar disorder, and dysthymia),anxiety, panic disorder, generalized anxiety disorder, post traumaticstress disorder, premenstrual dysphoric disorder, fibromyalgia,agorophobia, attention deficit disorder (with and withouthyperactivity), obsessive compulsive disorder (includingtrichotillomania), social anxiety disorder, autism, schizophrenia,obesity, anorexia nervosa, bulimia nervosa, Gilles de la TouretteSyndrome, vasomotor flushing, cocaine and alcohol addiction, sexualdysfunction (including, but not limited to, premature ejaculation),borderline personality disorder, chronic fatigue syndrome, urinaryincontinence, pain (including, but not limited to, migraine, chronicback pain, phantom limb pain, central pain, neuopathic pain such asdiabetic neuropathy, and postherpetic neuropathy), Shy Drager syndrome,Raynaud's syndrome, Parkinson's disease, and epilepsy comprisingproviding to a patient an effective amount of ODV succinate. ODVsuccinate can also be administered to prevent relapse or recurrence ofdepression, to induce cognitive enhancement, to treat cognitiveimpairment, and in regimens for cessation of smoking or other tobaccouses. Additionally, ODV succinate can be administered to treathypothalamic amenorrhea in depressed and non-depressed human females.These methods include administering to a patient in need thereof, aneffective amount of ODV succinate or a substantially pure polymorph ofODV succinate, or mixtures thereof.

[0008] The present invention also provides four crystalline polymorphicforms of ODV succinate (hereinafter referred to as Forms I, II, III, andIV, respectively) and an amorphous form of ODV succinate. According to apreferred embodiment, the pharmaceutical composition of the presentinvention comprises at least about 20, 30, 40, 50, 60, 70, 80, 90, 95,96, 97, 98, 99, 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7, 99.8, or 99.9%by weight of Form I, II, III, or IV or the amorphous form of ODVsuccinate, based upon 100% total weight of ODV succinate in thepharmaceutical composition (or the total weight of crystalline ODVsuccinate in the pharmaceutical composition).

[0009] Another embodiment is a method for preparing the free base ofO-desemthyl-venlafaxine by demethylating venlafaxine or a salt thereofwith an alkali metal salt of a trialkylborohydride.

BRIEF DESCRIPTION OF THE INVENTION

[0010]FIG. 1 is an X-ray powder diffractogram (XRPD) of Form I of ODVsuccinate prepared in Example 7.

[0011]FIG. 2 is an XRPD of Form II of ODV succinate prepared in Example8.

[0012]FIG. 3 is an XRPD of Form III of ODV succinate prepared in Example9.

[0013]FIG. 4 is an XRPD of Form IV of ODV succinate prepared in Example10.

[0014]FIG. 5 is an XRPD of the amorphous form of ODV succinate preparedin Example 11.

[0015]FIG. 6 are differential scanning calorimetry (DSC) analyses ofForms I, II, and IV and the amorphous form of ODV succinate from 25 to250° C. in hermetically-sealed pans at a scan rate of 10° C./minuteunder a nitrogen purge.

[0016]FIG. 7 is an XRPD of Form I of the ODV succinate prepared inExample 1.

[0017]FIG. 8 are thermogravimetric analyses (TGA) of Forms I, II, and IVand the amorphous form of ODV succinate heated from 25 to 300° C. at ascan rate of 10° C./minute under a nitrogen purge.

[0018]FIG. 9 is a graph of the rat intestinal permeability coefficient(Peff) experimentally determined in Example 14 and predicted human invivo fraction of dose absorbed (Fa (%)) for ODV succinate, metoprolol,glucose, and mannitol.

[0019]FIG. 10 is a graph of the Peff experimentally determined and Facalculated in Example 14 for ODV succinate absorbed in theduodenum-jejunum, ileum, and colon.

[0020]FIG. 11 is a graph of Peff experimentally determined and Facalculated in Example 14 for ODV fumarate, metoprolol, glucose, andmannitol.

[0021]FIG. 12 is a graph of the Peff experimentally determined and Facalculated in Example 14 for ODV fumarate absorbed in theduodenum-jejunum, ileum, and colon.

[0022]FIG. 13 is a comparison of the site specific absorption of ODVfumarate versus ODV succinate in the duodenum-jejunum, ileum, and colonin Example 14.

[0023]FIG. 14 is a reaction scheme for preparing the free base ofO-desmethyl-venlafaxine from venlafaxine with L-selectride.

DETAILED DESCRIPTION OF THE INVENTION

[0024] Definitions

[0025] The term “about” generally means within 10%, preferably within5%, and more preferably within 1% of a given value or range.Alternatively, the term “about” means within an acceptable standarderror of the mean, when considered by one of ordinary skill in the art.

[0026] The term “monohydrate” as used herein refers to a hydrate inwhich one molecule of water is associated with each molecule of ODVsuccinate.

[0027] The term “hemihydrate” as used herein refers to a hydrate inwhich one molecule of water is associated with every two molecules ofODV succinate.

[0028] The term “treat” as used herein refers to preventing,amelliorating, controlling, or curing the desired symptoms or disorders.

[0029] The term “substantially the same” when used to describe X-raypowder deffraction patterns, is meant to include patterns in which peaksare within a standard deviation of ±0.2° 2θ.

[0030] The present invention relates to a novel salt ofO-desmethyl-venlafaxine, O-desmethyl-venlafaxine succinate (hereinafterreferred to as “ODV succinate”). ODV succinate provides optimalproperties for formulation due to its high solubility, permeability, andbioavailability, and has the structural formula:

[0031] Succinic acid salts of O-desmethyl-venlafaxine exist asenantiomers and this invention includes racemic mixtures as well asstereoisomerically pure forms of the same. The term “ODV succinate” asused herein refers to racemic mixtures and stereoisomerically pure formsof ODV succinate, unless otherwise indicated.

[0032] The term “stereoisomerically pure” refers to compounds which arecomprised of a greater proportion of the desired isomer than of theoptical antipode. A stereoisomerically pure compound is generally madeup of at least about 90% of the desired isomer, based upon 100% totalweight of ODV succinate.

[0033] Succinic acid is a dicarboxylic acid and the invention thereforeincludes both salts in which the ratio of O-desmethyl-venlafaxine toacid (by mole) is 1:1 (i.e., a monosuccinate) and salts in which theratio of O-desmethyl-venlafaxine to acid (by mole) is 2:1 (i.e., a bisisuccinate), as well as mixed salts, with for example an alkali metal orammonium cation. The invention also includes mixtures of ODV succinateand the free base of O-desmethyl-venlafaxine. The crystalline polymorphs(i.e. Forms I, II, III, and IV) and the amorphous form of ODV succinatediscussed below are monosuccinate salts, i.e., the molar ratio ofO-desmethyl-venlafaxine to acid is 1:1. Salts of the present inventioncan be crystalline and may exist as more than one polymorph. Eachpolymorph forms another aspect of the invention. Hydrates as well asanhydrous forms of the salt are also encompassed by the invention. Inparticular the monohydrate form of O-desmethyl venlafaxine succinate ispreferred.

[0034] ODV succinate generally has a solubility in water of greater than30 mg/mL. Preferably, the aqueous solubility of the ODV succinate is atleast 25, 30, 32, 35, 40, or 45 mg/mL at 25° C.

[0035] Succinic acid salts may be formed by contacting stoichiometricamounts of the acid with O-desmethy-venlafaxine free base.Alternatively, the acid may be used in excess, usually no more than 1.5equivalents. Preferably the base and/or the acid are in solution, morepreferably both are in solution.

[0036] The crystalline salt may be prepared by directly crystallizingfrom a solvent. Improved yield may be obtained by evaporation of some orall of the solvent or by crystallization at elevated temperaturesfollowed by controlled cooling, preferably in stages. Careful control ofprecipitation temperature and seeding may be used to improve thereproducibility of the production process and the particle sizedistribution and form of the product.

[0037] Form I

[0038] Crystalline polymorph Form I of ODV succinate is a monohydrateand is stable at room temperature. Form I is physically stable up to atleast about 105° C. and at 5-95% relative humidity. According todifferential scanning calorimetry (DSC), Form I has an endotherm atabout 131° C. (see FIG. 6). Form I of ODV succinate has an XRPD patternsubstantially identical to that shown in FIGS. 1 (ground Form I) and 7(unground Form I). Peak locations and intensities for the XRPD patternin FIG. 1 are provided in Table 1 below. TABLE 1 Characteristic XRPDPeaks (expressed in degrees 2θ ± 0.2° 2θ) and Relative Intensities ofDiffraction Lines for Form I of ODV Succinate Degrees 2θ ± 0.2° 2θ I/I₁10.20 17 14.91 12 20.56 18 22.13 11 23.71 13 24.60 14 25.79 100

[0039] In particular, the peaks (expressed in degrees 2θ±0.2° 2θ) at10.20, 14.91, 20.56, 22.13, 23.71, 24.60, and 25.79 are characteristicof Form I.

[0040] Form I may be prepared from the free base ofO-desmethyl-venlafaxine as follows. The free base ofO-desmethyl-venlafaxine and succinic acid are dissolved in aqueousacetone. The resulting solution may optionally be filtered to remove anybyproducts, such as those produced during the preparation of the freebase of O-desmethyl-venlafaxine. The solution is then slowly cooled(e.g., for 3 hours or longer) to yield Form I of ODV succinate. Thecrystals of Form I may be recovered by any method known in the art.

[0041] Form I can also be prepared by preparing a slurry containing (a)Form I and (b) Form II, Form III, or a mixture thereof with (c) acetone,acetonitrile, a mixture of acetonitrile and water (e.g., a 9:1 mixture),or a mixture of ethanol and toluene (e.g., a 1:1 mixture) at ambienttemperature.

[0042] Any crystals prepared by the aforementioned methods may berecovered by technique known to those silled in the art, such as, forexample, filtration.

[0043] Form II

[0044] Crystalline polymorph Form II of ODV succinate is a monohydrateand is more thermally stable than Form III. According to DSC, Form IIhas an endotherm at about 127° C. (see FIG. 6). Form II of ODV succinatehas an XRPD pattern substantially identical to that shown in FIG. 2.Peak locations and intensities for the XRPD pattern in FIG. 2 areprovided in Table 2 below. TABLE 2 Characteristic XRPD Peaks (expressedin degrees 2θ ± 0.2° 2θ) and Relative Intensities of Diffraction Linesfor Form II of ODV Succinate Degrees 2θ ± 0.2° 2θ I/I₁ 10.25 22 13.18 1414.04 10 14.35 35 14.66 18 16.68 52 17.67 29 19.24 29 20.38 16 20.56 2523.41 24 23.78 16 24.57 13 25.13 10 25.80 100 31.78 14

[0045] In particular, the peaks (expressed in degrees 2θ±0.2° 2θ) at13.18, 14.04, 14.35, 14.66, 16.68, 17.67, 19.24, 25.13, and 31.78 arecharacteristic of Form II.

[0046] Form II can be prepared by rotary evaporation of Form I dissolvedin acetone.

[0047] Form II can also be prepared by slow cooling of either saturatedacetone or 95:5 ethanol:water solutions of Form I of ODV succinate.According to one embodiment, slow cooling is performed as follows. Amixture of the solvent and Form I of ODV succinate is prepared andheated and stirred on a hotplate (preferably set at 60-75° C.). Solventis added until the ODV succinate is nearly all dissolved. The resultingmixture is optionally filtered (e.g., through a 0.2-μm nylon filter)into a clean vial pre-warmed, preferably on the same hotplate. The heatsource is turned off, and the hotplate and vial are allowed to cool toambient temperature. The vial is then allowed to stand at ambienttemperature overnight. If no solids are generated, the vial is placed ina refrigerator for at least one day. Again, if no solids are generated,the vial is placed in a freezer for at least one day. Any solids areremoved by vacuum filtration and allowed to air dry. In cases where nosolid is obtained, a portion of the solvent is allowed to evaporate, andthe procedure is repeated with heating and filtering.

[0048] Yet another method for preparing Form II is by precipitating FormI of ODV succinate from a solvent/anti-solvent mixture ofethanol/hexanes. Suitable solvents include those in which ODV succinatehas a solubility of greater than 1 mg/mL. Suitable anti-solvents includethose in which ODV succinate has low solubility, e.g., a solubility ofless than 1 mg/mL. According to one embodiment, the solvent is saturatedwith ODV succinate. The mixture is heated, if necessary, to dissolve theODV succinate. The mixture is filtered (e.g., through a 0.2 μm nylonfilter) into a vial of cold anti-solvent (e.g., a solvent in which ODVsuccinate has a solubility of less than 0.1%). The resulting mixture maybe placed in a freezer to increase the yield.

[0049] Form II can be prepared by slow evaporation of Form I of ODVsuccinate from water. For example, Form I of ODV succinate may bedissolved in water and then left in a perforated container at ambienttemperature to form crystalline polymorph Form II.

[0050] Form II can be prepared by fast evaporation of Form I of ODVsuccinate from acetonitrile or ethanol/hexanes or ethanol/chloroformmother liquors. For example, Form I of ODV succinate may be dissolved inthe solvent and then left in an open container at ambient temperature toform crystalline polymorph Form II.

[0051] Form II can be prepared by rapid cooling of an aqueous oraqueous/acetone solution of ODV succinate. Rapid cooling can beperformed by any method known in the art, such as, for example, byapplying a vacuum and/or an ice or ice/water bath.

[0052] Form II can also be prepared by subjecting the amorphous form ofODV succinate to 75% or greater relative humidity (e.g., at roomtemperature).

[0053] Any crystals prepared by the aforementioned methods may berecovered by known techniques.

[0054] Form III

[0055] Crystalline polymorph Form III of ODV succinate is a hydrate. Themolar ratio of water to ODV succinate is less than 1 but more than ½(i.e., Form III of ODV succinate is between a hemihydrate and amonohydrate). Form III of ODV succinate has an XRPD patternsubstantially identical to that shown in FIG. 3. Peak locations andintensities for the XRPD pattern in FIG. 3 are provided in Table 3below. TABLE 3 Characteristic XRPD Peaks (expressed in degrees 2θ ± 0.2°2θ) and Relative Intensities of Diffraction Lines for Form III of ODVSuccinate Degrees 2θ ± 0.2° 2θ I/I₁ 10.36 23 13.74 11 14.40 20 14.68 1814.96 16 16.75 49 17.48 17 17.76 17 19.26 24 20.42 13 20.74 20 22.55 1123.58 16 23.82 20 24.92 12 26.00 100 31.86 17 32.42 10

[0056] In particular, the peaks (expressed in degrees 2θ±0.2° 2θ) atabout 13.74, 22.55, and 32.42 are characteristic of Form III.

[0057] Form III can be prepared by ball milling or cryo-grinding Form Iof ODV succinate. Ball milling is performed by placing a ball in acylinder with the ODV succinate and then shaking the cylinder.Cryo-grinding is performed by placing the ODV succinate in a cylinderand shaking the cylinder while maintaining the temperature of thecylinder at cryogenic temperatures (e.g., at <−90° C.).

[0058] Any crystals prepared by the aforementioned methods may berecovered by any known technique.

[0059] Form IV

[0060] Crystalline polymorph Form IV of ODV succinate is anhydrous.According to DSC, Form IV has an endotherm at about 145° C. (see FIG.6). Form IV of ODV succinate has an XRPD pattern substantially identicalto that shown in FIG. 4. Peak locations and intensities for the XRPDpattern in FIG. 4 are provided in Table 4 below. TABLE 4 CharacteristicXRPD Peaks (expressed in degrees 2θ ± 0.2° 2θ) and Relative Intensitiesof Diffraction Lines for Form IV of ODV Succinate Degrees 2θ ± 0.2° 2θI/I₁ 10.46 36 11.29 15 13.69 10 14.48 60 15.17 18 16.62 74 17.22 1417.61 42 19.22 10 19.64 48 20.91 83 21.61 33 22.55 12 23.84 89 24.77 2125.34 15 25.92 21 26.40 100 28.86 24 29.80 12 30.60 21 33.17 10 36.85 2137.70 12

[0061] In particular, the peaks (expressed in degrees 2θ±0.2° 2θ) atabout 11.29, 17.22, 19.64, 20.91, 21.61, 28.86, 29.80, 30.60, 36.85, and37.70 are characteristic of Form IV.

[0062] Form IV can be prepared by slurrying equal amounts of Form I andForm II in acetonitrile at about 54° C. for several days (e.g., eightdays), filtering, and heating the resulting solid for 18 hours at about120° C. The crystals can be recovered by any method known in the art.

[0063] Amorphous Form

[0064] The amorphous form of ODV succinate has an XRPD patternsubstantially identical to that shown in FIG. 5. FIG. 5 shows anamorphous form of ODV succinate. The glass transition (T_(g)) onset forthe amorphous form occurs at 18° C. According to DSC, the amorphous formundergoes a major endotherm at about 120° C. (see FIG. 6). Without beingbound by any theory, the inventors believe that the amorphous form wasconverted into a crystalline form before reaching 120° C., sinceamorphous forms typically do not exhibit endotherms, while crystallineforms do.

[0065] The amorphous form can be produced by forming a melt by heatingForms I, II, III, or IV, or a mixture thereof and cooling the melt toform a glass. For example, the amorphous form can be prepared by holdingForms I, II, III, or IV or a mixture thereof at about 150° C. for about6 to about 18 minutes to form a melt and then cooling the melt to form aglass. The cooling can be done slowly or rapidly (e.g., by crashcooling).

[0066] The amorphous form can be converted to Form II by placing theamorphous material in a high relative humidity environment (e.g.,greater than about 50 or about 75% relative humidity).

[0067] Preparation of ODV Free Base

[0068] O-desmethyl-venlafaxine (ODV) free base may be prepared accordingto the general procedures outlined in U.S. Pat. No. 4,535,186.

[0069] Another method of preparing ODV free base is by demethylating acompound of Formula I (venlafaxine) to provide a compound of Formula IIas described in Scheme I below.

[0070] As described in Scheme I the starting material, venlafaxine(Formula I), is demethylated. Venlafaxine may be prepared in accordancewith procedures known in the art, such as those described in U.S. Pat.No. 4,535,186, which is herein incorporated by reference.

[0071] Demethylation is performed using a high molecular weight alkane,arene, or arylalkyl thiolate anion, such as straight or branched chainalkane thiolate anions having 8 to 20 carbon atoms, mono or bicyclicarene thiolate anions having 6 to 10 carbon atoms, or mono or bicyclicarylalkyl thiolate anions having 7 to 12 carbon atoms in the presence ofa protic or aprotic solvent. Optionally, a base such as an alkoxidecomprised of a straight or branched chain alkyl group of from 1 to 6carbon atoms may be present to generate the thiolate anion.

[0072] Preferably the aliphatic thiol has from 10 to 20 carbon atoms andmost preferably the aliphatic thiol is dodecanethiol. The aromatic thiolis preferably benzenethiol. The arylalkyl thiolate anion is preferablytoluenethiol or naphthylmethanethiol.

[0073] When present, the alkoxide is preferably a lower alkoxide(methoxide, ethoxide and the like) such as sodium methoxide (sodiummethylate, sodium methanolate).

[0074] The solvent is preferably a hydroxylic or ethereal solvent, andmore preferably an alcohol, ethylene glycol or ether of ethylene glycol.Ethers of ethylene glycol include, but are not limited to,ethyleneglycol monoethylether, triethyleneglycoldimethylether andpolyethylene glycol. Preferably, the solvent is an inert, polar, highboiling point ether of ethylene glycol such as polyethylene glycol andmost preferably PEG 400 (polyethylene glycol having a molecular weightrange of from about 380-420).

[0075] The reaction is performed at a temperature of from about 150° C.to about 220° C., more preferably from about 170° C. to about 220° C.,and most preferably from about 180° C. to about 200° C. The reaction isgenerally allowed to progress until, ideally, not more than 1%venlafaxine remains. In some aspects of the invention the reaction iscomplete in from about 2 hours to about 5 hours and more preferably infrom about 2 to about 3.5 hours.

[0076] In preferred embodiments of this method, venlafaxine base isdissolved in polyethylene glycol 400 containing dodecanethiol and sodiummethylate as a solution in methanol as the temperature is increased tofrom about 180° C. to about 200° C., with stirring for about 2 to about3.5 hours.

[0077] Thereafter the reaction mixture is cooled to between about 65° C.and about 75° C. and an alcohol may be added as a diluent beforeneutralization to the isoelectric point (about pH 9.5 to about pH 10.0)with an appropriate neutralization agent such as hydrochloric acid. Thealcoholic medium may also aid in the crystallization of the product asneutralization is initiated.

[0078] Preferably the alcohol comprises a straight or branched chainalkyl group of 1 to 6 carbon atoms, such as methanol, ethanol,isopropanol, butanol, and the like, and mixtures thereof. In somepreferred embodiments of this method, the alcohol is isopropanol.

[0079] Yields of this method are greater than about 75% and generallyfrom about 85% to greater than 90%.

[0080] Yet another method of preparing ODV free base is by demethylatingvenlafaxine or a salt thereof (e.g., a non-reducible salt ofvenlafaxine, such as the hydrochloride salt) with an alkali metal saltof a trialkylborohydride. The alkyl groups in trialkylorohydride canindependently be C₁-C₆ alkyl and preferably are independently C₁-C₄alkyl. The alkyl substituents on the trialkylborohydride can be the sameor different. Suitable alkali metals include, but are not limited to,lithium, sodium, and potassium. Suitable trialkylborohydrides include,but are not limited to, selectride (tri-sec-butylborohydride) ortriethylborohydride. Non-limiting examples of suitable salts includeL-selectride, K-selectride, lithium triethylborohydride, and potassiumtriethylborohydride. Preferred salts include, but are not limited to,L-selectride and lithium triethylborohydride. A more preferred salt isL-selectride.

[0081] Generally, the demethylation process is performed in one or moreof the following solvents: 1,2-dimethoxyethane, tetrahydrofuran (THF),1,2-dethoxyethane and diglyme (bis (2-methoxyethyl) ether). The reactionis typically performed at or less than the boiling point of the solvent.Preferably, the reaction is performed at a temperature of from about 60to about 140° C., more preferably from about 80 to about 100° C., andeven more preferably from about 85 to about 95° C. The reaction isgenerally performed until the majority of venlafaxine has beendemethylated and preferably until at least 80, 90, 95, or 99% of thevenlafaxine has been demethylated. Broadly, the reaction is performedfor from about 8 to about 48 hours. According to one embodiment, thereaction is performed for from about 12 to about 36 hours and preferablyfor about 24 hours.

[0082] The reaction results in an alkali metal salt ofO-desmethyl-venlafaxine. The alkali metal salt can be converted to itsfree base by methods known in the art, such as neutralization with acid(e.g., to the isoelectric point).

[0083] This process for demethylating venlafaxine does not change theoptical activity of the venlafaxine starting material. In other words,if the starting material is a racemic mixture of venlafaxine, theproduct of this demethylation process will also be a racemic mixture. Ifthe starting material is an optically pure enantiomer, the product ofthis demethylation process will also be the same optically pureenantiomer.

[0084] An example of this reaction scheme for producingO-desmethyl-venlafaxine free base is shown in FIG. 14.

[0085] This process for demethylating venlafaxine can produce the freebase of ODV in substantially pure form (e.g., with <0.5, 0.4, 0.3, 0.2,0.1, 0.09, 0.08, 0.07, 0.06, or 0.05% of impurities (w/w) (excludinginorganics) as measured by HPLC).

[0086] Demethylation with a trialkylaborohydride produces varioushazardous boron containing byproducts. For example, use of L-selectrideresults in the formation of tris(1-methylpropyl)borane andtris(1-methylpropyl)boroxin as byproducts. These byproducts may bedeactivated (or stabilized) by oxidation and, optionally, hydrolysis (ofintermediate borate esters). Oxidation may be performed by reacting theboron containing byproducts with an oxidizing agent, such as hydrogenperoxide, perborates (e.g., sodium perborate), or a mixture thereof. Apreferred oxidizing agent is an alkaline perborate solution (e.g., anaqueous solution containing sodium hydroxide and sodium perboratetetrahydrate). Preferably, the boron containing byproducts are added tothe oxidizing agent or a solution comprising the oxidizing agent.

[0087] As described in Reviews in Contemporary Pharmacology, Volume 9(5)page 293-302 (1998), incorporated by reference in its entirety,O-desmethyl-venlafaxine has the following pharmacological profile shownin Table 5 below. TABLE 5 O-desmethylvenlafaxine Effect (in vivo)Reversal of Reserpine-Induce Hypothermia 3 (minimum effect; mg/kg i.p.)Effect (in vitro) Inhibition of amine reuptake (IC50; uM) Norepinephrine1.16 Serotonin 0.18 Dopamine 13.4 Affinity for Various Neuroreceptors (%inhibition at 1 uM) D2 6 Cholinergic 7 Adrenergic α 0 Histamine H1 0Opiate 7

[0088] Thus, compounds, compositions and methods of the presentinvention can be used to treat or prevent central nervous systemdisorders including, but not limited to depression (including but notlimited to major depressive disorder, bipolar disorder and dysthymia),fibromyalgia, anxiety, panic disorder, agoraphobia, post traumaticstress disorder, premenstrual dysphoric disorder (also known aspremenstrual syndrome), attention deficit disorder (with and withouthyperactivity), obsessive compulsive disorder (includingtrichotillomania), social anxiety disorder, generalized anxietydisorder, autism, schizophrenia, obesity, anorexia nervosa, bulimianervosa, Gilles de la Tourette Syndrome, vasomotor flushing, cocaine andalcohol addiction, sexual dysfunction, (including prematureejaculation), borderline personality disorder, chronic fatigue syndrome,incontinence (including fecal incontinence, overflow incontinence,passive incontinence, reflex incontinence, stress urinary incontinence,urge incontinence, urinary exertional incontinence and urinaryincontinence), pain (including but not limited to migraine, chronic backpain, phantom limb pain, central pain, neuropathic pain such as diabeticneuropathy, and postherpetic neuropathy), Shy Drager syndrome, Raynaud'ssyndrome, Parkinson's Disease, epilepsy, and others. Compounds andcompositions of the present invention can also be used for preventingrelapse or recurrence of depression; to treat cognitive impairment; forthe inducement of cognitive enhancement in patient suffering from seniledementia, Alzheimer's disease, memory loss, amnesia and amnesiasyndrome; and in regimens for cessation of smoking or other tobaccouses. Additionally, compounds and compositions of the present inventioncan be used for treating hypothalamic amenorrhea in depressed andnon-depressed human females.

[0089] In some preferred embodiments of the invention,O-desmethyl-venlafaxine succinate is useful for the treatment ofdepression, anxiety, panic disorder, generalized anxiety disorder, posttraumatic stress and premenstrual dysphoric disorder.

[0090] This invention provides methods of treating, preventing,inhibiting or alleviating each of the maladies listed above in a mammal,preferably in a human, the methods comprising administering an effectiveamount of a compound of the invention to a mammal in need thereof. Aneffective amount is an amount sufficient to prevent, inhibit, oralleviate one or more symptoms of the aforementioned conditions.

[0091] The dosage amount useful to treat, prevent, inhibit or alleviateeach of the aforementioned conditions will vary with the severity of thecondition to be treated and the route of administration. The dose, anddose frequency will also vary according to age, body weight, responseand past medical history of the individual human patient. In generallythe recommended daily dose range for the conditions described herein liewithin the range of 10 mg to about 1000 mg O-desmethylvenlafaxine perday and more preferably within the range of about 15 mg to about 350mg/day and still more preferably from about 15 mg to about 140 mg/day.In other embodiments of the invention the dosage will range from about30 mg to about 90 mg/day. Dosage is described in terms of the free baseand is adjusted accordingly for the succinate salt. In managing thepatient, is generally preferred that the therapy be initiated at a lowerdose and increased if necessary. Dosages for non-human patients can beadjusted accordingly by one skilled in the art.

[0092] Another embodiment of the invention is a method of lowering theincidence of nauseau, vomiting, diarrhea, abdominal pain, headache,vaso-vagal malaise, and/or trismus resulting from the oraladministration of venlafaxine, O-desmethylvenlafaxine, or a salt ofO-desmethylvenlafaxine other than O-desmethylvenlafaxine succinate to apatient. The method includes orally administering to a patient in needthereof a therapeutically effective amount of O-desmethyl-venlafaxinesuccinate.

[0093] Yet another embodiment of the invention is a method of loweringthe incidence of nauseauu, vomiting, diarrhea, abdominal pain, headache,vaso-vagal malaise, and/or trismus resulting from the oraladministration of O-desmethylvenlafaxine succinate to a patient. Themethod includes orally administering to a patient in need thereof atherapeutically effective amount of a sustained release oral dosage formcomprising O-desmethyl-venlafaxine succinate having a peak blood plasmalevel of less than about 225 ng/ml.

[0094] O-desmethylvenlafaxine succinate may also be provided incombination with venlafaxine. The dosage of venlafaxine is preferablyabout 75 mg to about 350 mg/day and more preferably about 75 mg to about225 mg/day. Still more preferably the dosage of venlafaxine is about 75mg to about 150 mg/day. The ratio of O-desmethylvenlafaxine tovenlafaxine will vary from patient to patient depending upon a patient'sresponse rate, but generally will be at least 6:1 O-desmethylvenlafaxineto venlafaxine.

[0095] Any suitable route of administration can be employed forproviding the patient with an effective amount of O-desmethylvenlafaxinesuccinate. For example, oral, mucosal (e.g. nasal, sublingual, buccal,rectal or vaginal), parental (e.g. intravenous or intramuscular),transdermal, and subcutaneous routes can be employed. Preferred routesof administration include oral, transdermal and mucosal.

[0096] O-desmethyl venlafaxine succinate can be combined with apharmaceutical carrier or excipient (e.g., pharmaceutically acceptablecarriers and excipients) according to conventional pharmaceuticalcompounding technique to form a pharmaceutical composition or dosageform. Suitable pharmaceutically acceptable carriers and excipientsinclude, but are not limited to, those described in Remington's, TheScience and Practice of Pharmacy, (Gennaro, A. R., ed., 19^(th) edition,1995, Mack Pub. Co.) which is herein incorporated by reference. Thephrase “pharmaceutically acceptable” refers to additives or compositionsthat are physiologically tolerable and do not typically produce anallergic or similar untoward reaction, such as gastric upset, dizzinessand the like, when administered to an animal, such as a mammal (e.g., ahuman). For oral liquid pharmaceutical compositions, pharmaceuticalcarriers and excipients can include, but are not limited to water,glycols, oils, alcohols, flavoring agents, preservatives, coloringagents, and the like. Oral solid pharmaceutical compositions mayinclude, but are not limited to starches, sugars, microcrystallinecellulose, diluents, granulating agents, lubricants, binders anddisintegrating agents. The pharmaceutical composition and dosage formmay also include venlafaxine or a salt thereof as discussed above.

[0097] According to one embodiment, the majority of ODV succinateparticles in a pharmaceutical composition or dosage form of the presentinvention have a particle size between 45 and 400 microns. Preferably,more than 60 or 65% of the particles have a particle size between 45 and400 microns.

[0098] Dosage forms include, but are not limited to tablets, capsules,troches, lozenges, dispersions, suspensions, suppositories, ointments,cataplasms, pastes, powders, creams, solutions, capsules (includingencapsulated spheroids), and patches. The dosage forms may also includeimmediate release as well as formulations adapted for controlled,sustained, extended, or delayed release. Most preferably tablets andcapsules are the dosage form. Tablets and spheroids may be coated bystandard aqueous and nonaqueous techniques as required.

[0099] Each dosage form generally contains from about 15 to about 350 mgof ODV succinate (as measured by the free base equivalent). Morepreferably, each dosage form contains from about 30 to about 200 mg ofODV succinate (as measured by the free base equivalent) and even morepreferably from about 75 to about 150 mg of ODV succinate (as measuredby the free base equivalent).

[0100] According to one preferred embodiment, the pharmaceuticalcomposition is an extended release formulation, such as that describedin U.S. Pat. No. 6,274,171, which is herein incorporated by reference.For example, an extended release formulation may comprise spheroidscomprised of ODV succinate, microcrystalline cellulose, and, optionally,hydroxypropylmethylcellulose. The spheroids are preferably coated with afilm coating composition comprised of ethyl cellulose andhydroxypropylmethylcellulose.

[0101] According to another preferred embodiment, the pharmaceuticalcomposition is a sustained release formulation (e.g., in the form of atablet). The sustained release formulation may comprise ODV succinate, arate controlling polymer material (i.e., a material which controls therate at which the ODV succinate is released), and, optionally, otheradjuvants. Suitable rate controlling polymer materials include, but arenot limited to, hydroxyalkyl cellulose, such as hydroxypropyl celluloseand hydroxypropyl methyl cellulose (HPMC); poly(ethylene) oxide; alkylcellulose, such as ethyl cellulose and methyl cellulose; carboxymethylcellulose; hydrophilic cellulose derivatives; and polyethylene glycol.The sustained release formulation comprises from about 30 w/w to about50% w/w of ODV succinate and from about 25 w/w to about 70% w/w of arate controlling polymer material. Optionally, the sustained releaseformulation may further comprise from about 0.5 w/w to about 10% w/w andpreferably from about 2 w/w to about 10% of microcrystalline cellulose.A preferred sustained release formulation comprises from about 32 w/w toabout 44% w/w of ODV succinate and from about 45 w/w to about 66% w/w ofhydroxyprpopyl methylcellulose. Typically, the sustained releaseformulation provides sustained therapeutically effective plasma levelsover at least a 16 or 20 hour period. The peak serum levels during the16 or 20 hour period are generally up to 150 ng/ml. The sustainedrelease formulation also shows a reduced level of nausea, vomiting,diarrhea, abdominal pain, headache, vaso-vagal malaise, and/or trismus.

[0102] The following examples are illustrative but are not meant to belimiting of the present invention.

EXAMPLE 1 Preparation of Form I of ODV Succinate

[0103] Acetone (2111 mL), water (667 mL) and O-desmethyl-venlafaxine(250.0 g, 0.949 mol) were mixed to form a thick white suspension whichwas stirred at 23° C. for 0.5 hour. Succinic acid (115.5 g, 0.978 mol)was added with acetone (236 mL) and water (75 mL). The suspension washeated to 58° C. and stirred at this temperature for 30 minutes. Thereaction mixture was filtered and allowed to cool to 30-34° C. Thesuspension was stirred at 30-31° C. for 3 hours then cooled to 0-5° C.and stirred at this temperature for a further hour. The solids wereisolated by filtration and the wet cake dried at 30° C. for 12 hours (50mm Hg) then 40° C. for 24 hours (50 mm Hg) to affordO-des-methyl-Venlafaxine succinate monohydrate as white crystals (325.5g, 85.7%). mp: 122.3 C and 139.6 C

[0104]¹H NMR (300 MHz, DMSO-d₆) 10-9 (bs, 2H), 7.00 (d, J=8.2 Hz, 2H),6.65 (d, J=8.2 Hz, 2H), 3.4-3.2 (bs, 1H), 3.12 (dd, J=7.0, 12.2 Hz, 1H),2.74 (t, J=8.7 Hz, 1H), 2.7-2.58 (m, 1H), 2.50 (s, 3H), 2.36 (s, 3H),2.28 (s, 4H), 1.50-1.25 (m, 6H), 1.20-0.80 (4H). 99.40% Purity (byHPLC).

[0105] An XRPD pattern for the (unground) crystals prepared is shown inFIG. 7. Characteristic XRPD peaks are shown in Table 6 below. TABLE 6X-ray powder diffractogram (CuK2α) Angle (° 2θ) Relative Intensity 5.28530.6 10.435 54.6 20.680 10.4 20.850 23.2 25.660 6.6 25.955 55.5 26.125100.0

[0106] The crystals of Form I examined in FIG. 7 were not ground, whilethose in FIG. 1 were ground before being examined. Without being boundby any theory, the inventors theorize that the XRPD for the ungroundcrystals differed from that of the ground crystals due to the preferredorientation of the unground crystals.

[0107] Bulk Density: 0.369 gms/mL

[0108] Solubility in water: 32.2 mg/ml at 25° C.

[0109] The aqueous solubility (reported above) of Form I of ODVsuccinate was determined according to the following procedure.

[0110] Materials

[0111] Spectrophotometer—Capable of isolating a bandwidth of 2 nm orless at the wavelength of maximum absorbance, and of measuringabsorbances in the 0.0 to 1.0 range with a precision of 0.01. A CaryModel 219 spectrophotometer or equivalent is suitable.

[0112] Cells—Silica, 1 cm.

[0113] Filters—0.45 micron Nylon filters which are chemical resistant orequivalent.

[0114] Bottles—Glass screw top bottles having a 15 mL or greatercapacity.

[0115] Shaker—A lateral shaker, wrist shaker, or a vibrator which willnot generate heat is suitable.

[0116] Sample Preparation

[0117] A. For Non UV Absorbing Solvents

[0118] 1. To a bottle weigh an amount of sample equivalent toapproximately 1½ times the solubility.

[0119] 2. Pipet 10.0 mL of water into the bottle and secure cap tightly.

[0120] 3. Agitate the bottles at ambient room temperature for at least16 hours.

[0121] 4. Obtain a clear filtrate layer by either centrifugation otfiltration being careful to avoid evaporation.

[0122] 5. Quantitatively transfer the solution to a volumetric flask anddilute to volume with water.

[0123] 6. Blank the instrument for water.

[0124] 7. Make quantitative dilutions to arrive at a suitableconcentration for measurement.

[0125] B. For UV Absorbing Solvents

[0126] 1. To a bottle, weigh an amount of sample equivalent toapproximately 1½ times the solubility.

[0127] 2. Pipet 10.0 mL of water into the bottle and secure a captightly.

[0128] 3. Agitate the bottles at ambient room temperature for at least16 hours.

[0129] 4. Obtain a clear filtrate layer by either centrifugation orfiltration being careful to avoid evaporation.

[0130] 5. Evaporate an accurate amount of solvent on a steam bath andredissolve the residue, in the solvent used to prepare the standard.Quantitatively transfer to a volumetric flask with the same solvent usedin preparing the standard solution.

[0131] 6. Make dilutions as necessary to obtain a concentration suitablefor quantitative measurement.

[0132] Procedure

[0133] 1. Obtain the spectra of the sample and standard preparationsbetween 350 and 200 nm, using water as the blank. The wavelength rangemay be varied depending upon the UV cut off of water.

[0134] 2. Calculate the aqueous solubility with the following equation:${{mg}\text{/}{mL}} = \frac{({As})({Ds})\left( {{Wg} - {Wt}} \right)(S)}{({Ar})({Dr})(V)}$

[0135] where

[0136] As=absorbance of the sample preparation

[0137] Ds—=dilution factor of the sample preparation, mL

[0138] Wg=gross weight of the reference standard and container, mg

[0139] Wt=tare weight, mg

[0140] S=strength of the reference standard, decimal

[0141] Ar=absorbance of the reference standard preparation

[0142] Dr=dilution factor of the reference standard preparation, mL

[0143] V=amount of solvent evaporated, mL

EXAMPLE 2

[0144] Hard Gelatin Capsule Dosage Form Ingredient mg/capsule % w/w ODVsuccinate 116.7 39.5 (75 as free base) Lactose Fast Flow 177.3 60.0Magnesium Stearate 1.5 0.5 Total 295.5 100.0

[0145] The active ingredient is sieved and blended with the listedexcipients. Suitably sized hard gelatin capsules are filled usingsuitable machinery and methods well known in the art. Other doses may beprepared by altering the fill weight and, if necessary, by changing thecapsule size to suit.

EXAMPLE 3

[0146] Preparation of O-desmethyl-venlafaxine Free Base

[0147] Dodecanethiol (122 g), venlafaxine (111 g), and a methanolicsolution of sodium methanolate (30%, 90 g) and PEG 400 are heated to190° C. The methanol is distilled off and the solution is stirred for 2hours at 190° C. Then the temperature is lowered, 2-propanol (450 g) isadded and the pH is adjusted to 9.5 with aqueous HCl. The precipitate iscollected by suction filtration, and the cake is washed with 2-propanol,toluene, 2-propanol and water. The wet O-desmethylvenlafaxine is driedin vacuo. Yield: 87 g.

[0148]¹H-NMR: (Gemini 200, Varian, 200 MHz) (DMSO-d6) δ=9.11 (s, br, 1H;OH), 6.98 (d, br, J=8.4, 2H; arom.), 6.65 (d, br, J=8.4, 2H; arom.),5.32 (s, br, 1H; OH), 3.00 (dd, J=12.3 and 8.5, 1H), 2.73 (dd, J=8.5 and6.3, 1H), 2.36 (dd, J=12.3 and 6.3, 1H) 2.15 (s, 6H, 2×Me), 1.7-0.8 (m,10H, c-hex).

EXAMPLE 4

[0149] Preparation of O-desmethyl-venlafaxine Free Base

[0150] Venlafaxine (5.6 g) and benzenethiol sodium salt (6.9 g) arecharged to PEG 400 (25 g). The reaction mixture is heated to 160° C. for5 hours. Then the temperature is lowered and water is added (60 g). ThepH is adjusted to 3.5 with H₃PO₄. The organic by-products are removed byextraction with heptanes (25 g). The pH of the aqueous layer is thenadjusted to 9.5 with aqueous ammonia. The precipitate is collected bysuction filtration, re-slurried in water (100 g), isolated by suctionfiltration and dried in vacuo. Yield 1 g.

[0151]¹H-NMR: (Gemini 200, Varian, 200 MHz) (DMSO-d6) δ=9.11 (s, br, 1H;OH), 6.98 (d, br, J=8.4, 2H; arom.), 6.65 (d, br, J=8.4, 2H; arom.),5.32 (s, br, 1H; OH), 3.00 (dd, J=12.3 and 8.5, 1H), 2.73 (dd, J=8.5 and6.3, 1H), 2.36 (dd, J=12.3 and 6.3, 1H) 2.15 (s, 6H, 2×Me), 1.7-0.8 (m,10H, c-hex).

EXAMPLE 5

[0152] Preparation of O-desmethyl-venlafaxine Free Base

[0153] Dodecanethiol (69 g), venlafaxine (55 g), and an ethanolicsolution of sodium ethanolate (21%, 82 g) are charged to a pressurevessel. The temperature is raised to 150° C. and the reaction mixture isstirred for 2 days. Then the temperature is lowered and the solution isfiltered. The pH of the filtrate is adjusted to 9.5 with aqueoushydrogen chloride. The crystals are collected by suction filtration. Thecake is washed with ethanol and dried in vacuo. Yield: 42 g

[0154]¹H-NMR: (Gemini 200, Varian, 200 MHz) (DMSO-d6) δ=9.11 (s, br, 1H;OH), 6.98 (d, br, J=8.4, 2H; arom.), 6.65 (d, br, J=8.4, 2H; arom.),5.32 (s, br, 1H; OH), 3.00 (dd, J=12.3 and 8.5, 1H), 2.73 (dd, J=8.5 and6.3, 1H), 2.36 (dd, J=12.3 and 6.3, 1H), 2.15 (s, 6H, 2×Me), 1.7-0.8 (m,10H, c-hex).

EXAMPLE 6

[0155] Preparation of O-desmethyl-venlafaxine Free Base

[0156] A 12 L multi-necked flask, equipped with a mechanical stirrer, athermometer, a 1 L pressure equalizing dropping funnel, and a Claisendistillation head equipped with a downward condenser attached to a 5 Lreceiver with a vacuum take-off, was placed in a heating mantle. Thesystem was purged with nitrogen and a nitrogen atmosphere wasmaintained. The distillation flask was charged with 4.00 L (4.00 mol,5.55 molar excess) of 1 M L-selectride. The dropping funnel was chargedwith a solution of 200.00 g (0.720 mol) of venlafaxine base in 0.6936 kg(800 mL) of anhydrous 1,2-dimethoxyethane while maintaining the nitrogenatmosphere. The solution of venlafaxine base was added to the stirredL-selectride solution over a period of 15 minutes using rinses of1,2-dimethoxyethane (2×400 mL, 2×0.3468 kg). Hydrogen was vented andbubbled through a dispersion tube into water. No significant temperaturechange occurred during the addition.

[0157] The dropping funnel was replaced with a similar 4 L funnelcharged with 2.4276 kg (2800 mL) of anhydrous 1,2-dimethoxyethane. Thesystem was again purged with nitrogen and a nitrogen atmosphere wasmaintained. The solution was heated and distilled at atmosphericpressure until the liquid level reached the 4 L mark and the reactionflask temperature was 84-85° C. While distilling, 2.4276 kg (2800 mL) of1,2-dimethoxyethane was added dropwise at a rate which maintained theliquid level at the 4.00 L level until the temperature in the reactionflask reached 93-94° C. A crystalline precipitate was observed. Thedistillate was discarded.

[0158] The stirred slurry of crystals was cooled to 90° C., the stirrerwas stopped, and the dropping funnel and distillation equipment wasremoved. The flask was then equipped with a reflux condenser fitted witha nitrogen inlet. The system was purged with nitrogen and a nitrogenatmosphere was maintained. The slurry was stirred and heated at refluxunder a nitrogen atmosphere for about 19 hours. The initial temperatureof the slurry at reflux was 94-96° C. and the final temperature was 97°C. Copious crystallization occurred. The slurry was cooled to roomtemperature.

[0159] 12 L of distilled water in a 20 L Duran flask was purged withnitrogen to remove oxygen and carbon dioxide. The purging was repeatedas necessary. This water is hereinafter referred to as “nitrogen purgeddistilled water”.

[0160] The heating mantle was removed and replaced with an ice/waterbath to bring the temperature of the reaction mixture to near roomtemperature. The flask was equipped with a 1000 mL pressure equalizingdropping funnel. The stirred reaction mixture was cooled with anice/alcohol bath to obtain a temperature of 15-20° C. While the nitrogenatmosphere was maintained, the reaction mixture was quenched by dropwiseaddition of 0.296 kg (296 mL) of the nitrogen purged distilled water.The addition was controlled so as to maintain the temperature below 25°C. The temperature rose to 15-24° C. as a result of an exotherm. Themixture was stirred at ambient temperature for about 1 hour. A thickgel-like precipitate, which was formed initially, was converted into acrystalline precipitate during this period. While the reaction mixturewas maintained in the nitrogen atmosphere, the flask was equipped with aClaisen distillation head, a downward condenser with a vacuum take-offand a 5 L receiving flask chilled in an ice/water bath. The stirredreaction mixture was distilled under pump vaccum (109-134 mm Hg) down tothe 2.80 L mark at a distillation flask temperature of 25-38° C. Thedistillate was discarded. 3.00 kg (3000 mL) of nitrogen purged distilledwater was added.

[0161] The stirred mixture was distilled under pump vacuum (113-187 mmHg) down to 2.80 L at a distillation flask temperature of 35-50° C. toform a biphasic mixture. The distillate (Distillate A) was discarded bythe Waste Treatment procedure described below. The warm biphasic mixture(35-40° C.) was transferred to a 4 L separatory funnel using rinses of600 mL of nitrogen purged distilled water and 0.5296 kg (600 mL) oftoluene. The two phases were mixed and then allowed to separate. A smallquantity of solid at the interface was discarded. The aqueous layer wasextracted consecutively with toluene (2×0.5196 kg, 2×600 mL) and heptane(0.5472 kg, 800 mL). The organic phases (Extract A) were discarded bythe Waste Treatment procedure described below. A sufficient amount ofnitrogen purged distilled water was added to the aqueous layer toachieve a volume of 3.60 L.

[0162] A 12 L multi-necked flask was equipped with a mechanical stirrer,a thermometer, and a condenser with a nitrogen inlet. The flask waspurged with nitrogen and a nitrogen atmosphere was maintained in theflask.

[0163] The 3.60 L aqueous layer was transferred to the empty 12 L flask.The stirred solution was cooled under nitrogen to 10-15° C. with anice/water bath. From a 1000 mL pressure equalizing dropping funnel, 410mL of 12 N hydrochloric acid was added dropwise to the stirred solutionwhile maintaining the temperature at 10-15° C. with the ice/water bathand until a pH of 3.5±0.2 was reached. A small precipitate was formed.

[0164] The resulting suspension was filtered through a Celite pad onpolypropylene cloth in a 19 cm Buchner funnel into a 5 L multi-neckedflask equipped with a mechanical stirrer, a thermometer, a condenserwith a nitrogen inlet and a 1000 mL pressure equalizing dropping funnel.The filter pad was washed with 300 mL of nitrogen purged distilledwater.

[0165] The filter funnel was removed. The system was flushed withnitrogen and again maintained in a nitrogen atmosphere. To the stirredsolution, 76 mL of 10 N sodium hydroxide was added from the droppingfunnel until a pH of 9.6±0.2 was reached. The resulting slurry ofcrystals was cooled to 5-10° C. and the slurry of crystals wasmaintained at 0-5° C. for about 1 hour.

[0166] The solid was collected on a polypropylene cloth in a 19 cmBuchner funnel. The filter cake was washed with 3×200 mL of nitrogenpurged distilled water. The filtrate was discarded.

[0167] A 12 L multi-necked flask was equipped with a mechanical stirrer,a thermometer, and a condenser with a nitrogen inlet. The flask waspurged with nitrogen and a nitrogen atmosphere was maintained in theflask. The flask was charged with 3000 mL of nitrogen purged distilledwater and cooled to 15-20° C. with an ice/water bath. The solidscollected on the polypropylene cloth were added to the stirred water inthe flask and stirred at 15-20° C. until a smooth suspension wasobtained (about 30 minutes).

[0168] The solid was collected on a polypropylene cloth in a 19 cmBuchner funnel using 600 mL of nitrogen purged distilled water tocomplete the transfer. The filter cake was washed with water (3×300 mL)and filtered. A dam was formed on top of the filter with a sheet oflatex rubber and an aspirator vacuum was applied to the filter flask forabout 5 hours. The white solid was dried in a vacuum oven under oil pumpvacuum at 80° C. for about 18 hours. The solid was crushed and re-driedif necessary to constant weight. The yield was 90.7% (172.3 g) (HPLCAnalysis: Strength or Purity (w/w): 98.8%, Impurities (excludinginorganics) (w/w): 0.046%, Ash (inorganics) (w/w): 0.14%).

[0169] Waste Treatment

[0170] The waste to be discarded contained byproducts, such astris(1-methylpropyl)-borane and tris(1-methylpropyl)-boroxin. A 22 L or50 L multi-necked flask was equipped with a mechanical stirrer, athermometer, and a condenser with a nitrogen inlet. The flask was purgedwith nitrogen using a Firestone valve and a nitrogen atmosphere wasmaintained in the flask.

[0171] Distillate A and Extract A were combined in the flask to obtain abiphasic mixture (4.00 L with 400 mL of an aqueous bottom phase) under anitrogen atmosphere. The stirrer was started and 600 mL of 10 N sodiumhydroxide and 600 mL of water were added. A slurry of sodium perboratetetrahydrate (1.848 kg, 12.01 moles, ˜3 equivalents per mole oftris(1-methylpropyl)borane) in 12 L of water was added in portions withice/water cooling over about 20 minutes to maintain the temperature at28-38° C. After the exotherm had subsided, the mixture was stirred at22-23° C. under a nitrogen atmosphere for about 18 hours. The soliddissolved and two liquid phases remained.

[0172] The stirrer was stopped and the phases were allowed to separate.The upper phase was examined by gas chromatography/mass spectrometry todetermine if any tris(1-methylpropyl)borane ortris(1-methylpropyl)boroxin was still detectable. If any was detected,80 g (0.52 mol) of sodium perborate was added as a slurry in 400 mL ofwater and the solution was stirred at 22-23° C. for about 18 hours. Oncetris(1-methylpropyl)borane and tris(1-methylpropyl)boroxin were nolonger detectable in the upper phase, the aqueous phase was checked forits oxidizing capability (for example, due to peroxides and excesssodium perborate) with starch iodide paper.

[0173] The phases of the solution were then separated. The top organiclayer was combined with other organic waste from the synthesis to bediscarded. The aqueous layer was combined with other aqueous waste fromthe synthesis to be discarded.

[0174] The following procedures were used in the Examples 7-11 below.

[0175] X-Ray Powder Diffraction

[0176] XRPD analyses were carried out on a Shimadzu XRD-6000 X-raypowder diffractometer using Cu Kα radiation. The instrument is equippedwith a fine focus X-ray tube. The tube power and amperage were set at 40kV and 40 mA, respectively. The divergence and scattering slits were at1° and the receiving slit was set at 0.15 mm. Diffracted radiation wasdetected by a Nal scintillation detector. A theta-two theta continuousscan at 3°/min (0.4 s/0.02° step) from 2.5 to 40° 2θ was used. A siliconstandard was analyzed each day to check the instrument alignment.

[0177] In cases where preferred orientation [vide infra] occurred duringX-ray powder diffraction, the ODV succinate was sometimes placed betweenfolded weighing paper, then ground with an agate pestle and re-analyzedby XRPD.

[0178] Thermogravimetric Analysis (TGA)

[0179] Thermogravimetric analysis was conduct on a TA Instruments 2950thermogravimetric analyzer. The calibration standards were nickel andAlumel™. Approximately 8-20 mg of sample were placed in the pan,accurately weighed, and inserted into the TG furnace. The samples wereheated under nitrogen at a rate of 10° C./min, up to a final temperatureof 300° C. Weight derivative (%/° C.) was used to determine total weightloss between 40° C. and the temperature at which the derivative was zero(usually 150° C.). The results of TGA for Examples 8-12 below are shownin FIG. 8.

[0180] Different Scanning Calorimetry

[0181] DSC analyses were carried out on a TA Instruments differentialscanning calorimeter 2920. Approximately 3-5 mg of sample was placedinto a DSC pan, and the weight accurately recorded. The pan washermetically sealed. Each sample was heated under nitrogen at a rate of10° C./min, up to final temperature of 250° C. Indium metal was used asthe calibration standard. Reported DSC temperatures are at thetransition maxima. The results of DSC for Examples 8, 9, 11, and 12below are shown in FIG. 6.

[0182] DSC Glass Transition

[0183] For studies of the glass transition temperature (T_(g)) of theamorphous material, the sample was heated under nitrogen at a rate of10° C./min up to a final temperature of 250° C. The sample pan washermetically sealed.

[0184] EXAMPLE 7

[0185] Preparation of Form I of ODV Succinate

[0186] A 5 L multi-necked flask, equipped with a stirrer, a thermometer,and a condenser, with a nitrogen inlet attached to a Firestone valvewere placed in a heating mantle. The system was purged with nitrogen anda nitrogen atmosphere was maintained. 1.668 kg (2111 mL) acetone and0.667 kg (667 mL) water were charged into the flask. The stirrer wasstarted and 0.250 kg (0.949 mol) O-desmethyl-venlafaxine free base(prepared as described in Example 6) were added. The suspension wasstirred for 30 minutes. 0.1155 kg (0.978 mol) succinic acid were addedand the transfer was completed with rinses of acetone (0.186 kg, 236 mL)and water (0.075 kg, 75 mL). The suspension was stirred, warmed to 60°C. (±30° C.), and maintained at 60° C. (±30° C.) while being stirred for30-60 minutes. A clear to cloudy solution was obtained. The mixture wasthen filtered through a filter comprised of polypropylene cloth with afilter paper underlay into a 5 L multi-necked flask equipped with amechanical stirrer, a thermometer, and a condenser fitted with a vacuumoutlet. The filter funnel was rinsed with warm (50-60° C.) aqueousacetone (24:76 v/v, 427 mL). The system was purged with nitrogen and thesolution was cooled to 30-35° C. to induce crystallization. The stirredslurry of crystals was maintained at that temperature for about 4 hours.The stirred slurry of crystals was cooled to 0-5° C. and maintained atthat temperature for about 1 hour. The crystals were collected on apolypropylene cloth filter with a filter paper underlay in a 15 cmfunnel. The filter cake was washed with cold (0-5° C.) aqueous acetone(24:76 v/v, 2×300 mL) and filtered for 5 minutes. A dam was formed ontop of the filter with a sheet of latex rubber. An aspirator was appliedto the filter cake for 1 hour. The weight of the filter cake was about0.351 kg. The product was dried under vacuum (50 mm Hg) at 30±5° C. for12 hours. The product was then dried under vacuum (50 mm Hg) at 45±5° C.for 24 hours.

[0187] An XRPD of the ODV succinate is shown in FIG. 1.

[0188] Alternative Preparation of Form I of ODV Succinate

[0189] A 5 L multi-necked flask equipped with a stirrer, a thermometer,and a condenser with a nitrogen inlet attached to a Firestone valve areplaced in a heating mantle. The system is purged with nitrogen and anitrogen atmosphere was maintained. 1.651 kg (2090 mL) acetone and 0.660kg (660 mL) water are charged into the flask. The stirrer is started and0.250 kg (0.949 mol) O-desmethyl-venlafaxine free base (prepared asdescribed in Example 6) are added. The suspension is stirred for 30minutes. 0.1155 kg (0.978 mol) succinic acid are added. The suspensionis stirred, warmed to 60° C. (±3° C.), and maintained at 60° C. (±3° C.)while being stirred for 30-60 minutes. The mixture is then filteredthrough a filter comprised of Celite on polypropylene cloth with afilter paper underlay into a 5 L multi-necked flask equipped with amechanical stirrer, a thermometer, and a condenser fitted with a vacuumoutlet. The filter funnel is rinsed with warm (50-60° C.) aqueousacetone (24:76 v/v, 427 mL). The system is purged with nitrogen and thesolution is cooled to 30-35° C. to induce crystallization. The stirredslurry of crystals is maintained at that temperature for about 4 hours.The stirred slurry of crystals is cooled to 0-5° C. and maintained atthat temperature for about 1 hour. The crystals are collected on apolypropylene cloth filter with a filter paper underlay in a 15 cmfunnel. The filter cake is washed with cold (0-5° C.) aqueous acetone(24:76 v/v, 2×300 mL) and filtered. A dam for the filter cake is formedwith a sheet of latex rubber. An aspirator is applied to the filter cakefor 1 hour. The weight of the wet cake is about 0.351 kg. The product isdried under vacuum (50 mm Hg) at 30±5° C. for 12 hours. The product isthen dried under vacuum (50 mm Hg) at 45±5° C. for 24 hours. The yieldwas 85.8% (325.2 g) (HPLC Analysis: Impurities (excluding inorganics)(w/w): 0.0%, Ash (inorganics) (w/w): 0.0%, Amount of any single impurity(w/w):<0.01%).

EXAMPLE 8

[0190] Preparation of Form II of ODV Succinate

[0191] Form II was prepared by dissolving 306.1 mg of Form I in 200 mlacetone, filtering the solution through a 0.2 um nylon disc followed byvacuum stripping the filtrate on a rotary evaporator at ambienttemperature.

[0192] An XRPD of the ODV succinate is shown in FIG. 2.

EXAMPLE 9

[0193] Preparation of Form III of ODV Succinate

[0194] Form III was prepared using two different milling techniques. Inthe first technique, ball-mill grinding, 290.2 mg of Form I was measuredinto a stainless steel cylinder with a ball, the sealed container wasplaced on a Retsch Mixer and milled for five minutes at a frequency of30/s. At the end of the cycle, a spatula was used to scrape materialfrom the walls. The procedure was repeated three times for a total milltime of 20 minutes. In the second technique, cryo-grinding, 40.5 mg ofForm I was charged to a stainless steel cylinder with a rod, the sealedcontainer was then placed in a SPEX Freezer mill maintained at −96degrees Celsius with liquid nitrogen. The material was milled for twominutes at a frequency of 10/s (20 impacts per second), then cooled fortwo minutes. The procedure was repeated two times for total mill time ofsix minutes.

[0195] An XRPD of the ODV succinate is shown in FIG. 3.

EXAMPLE 10

[0196] Preparation of Form IV of ODV Succinate

[0197] Form IV was prepared in the following manner: A mixture of equalamounts of Form I and Form II was charged to a saturated, 0.2um-filtered solution of acetonitrile-ODV succinate at 54 degreesCelsius. The mixture was agitated for a period of eight days. The slurrywas filtered and the recovered solids air-dried. The solids were thencharged to a 2-dram scintillating vial and heated for eighteen hours at120° C.

[0198] An XRPD of the ODV succinate is shown in FIG. 4.

EXAMPLE 11

[0199] Preparation of Amorphous Form of ODV Succinate

[0200] The amorphous form of ODV succinate was prepared by charging amixture of 854.1 mg of Forms I and 11 to an open, 20-ml scintillatingvial and then placing the vial in a 150° C. oil bath for about 18minutes.

[0201] An XRPD of the ODV succinate is shown in FIG. 5. According toDSC, the Tg onset occurs at 18° C.

EXAMPLE 12

[0202] Preparation of Form II of ODV Succinate

[0203] 56 g of O-desmethyl-venlafaxine, 26 g of succinic acid, 112 g ofacetone, and 112 g of purified water were charged into a container. Theresulting slurry was heated to reflux (about 62° C.) until a solutionformed. The solution was cooled slightly and 1.2 g of charcoal 2S wascharged. The solution was refluxed for about 15 minutes. The solutionwas filtered through a Seitz filter and the filter cake was washed with5 g of acetone. The hot solution was then charged into a bulb equippedwith a reflux condenser. A vacuum was applied from the top of thecondenser. The solution began to boil and crystallize. The solution wasstirred. The vacuum was applied until the slurry reached 20° C. Thesolution was cooled with an external ice bath to 5° C. The crystals wereisolated by suction filtration. The filter cake was washed with amixture of 11 g of purified water and 45 g of acetone. Air was suckedthrough the cake for about 2 hours. About 70 g of ODV succinate wasformed.

[0204] Alternative Preparation of Form II of ODV Succinate by FastCrystallization

[0205] A 2 L 4-neck flask was charged with O-desmethyl-venlafaxine (75.0g, 0.285 mol), acetone (627 mL), succinic acid (34.50 g, 0.29 mol), andwater (197.5 mL). The suspension was warmed to 60° C. and filteredthrough a pad of Celite. The filter pad was washed with a warm mixtureof acetone (97 mL) and water (30.6 mL). The filtrate was transferred toa clean 2 L flask rinsing with acetone (50 mL). The temperature of thesolution was 28° C. The solution was allowed to cool and crystallizationbegan at 23° C. The mixture was then rapidly cooled in an ice/water bathto 0-5° C. The mixture was stirred at 0-5° C. for 2 hours. The solidswere isolated by filtration and washed with cold aqueous acetone (2×200mL, 25:75 v/v water/acetone). The wet filter cake was dried in a vacuumoven at 35±5° C. (50 mm Hg) for 48 hours to yield ODV succinatemonohydrate as white crystals (89.5 g, 78.7%).

[0206]¹H NMR (300 MHz, DMSO-d₆) 10-9 (bs, 2H), 7.00 (d, J=8.2 Hz, 2H),6.65 (d, J=8.2 Hz, 2H), 3.4-3.2 (bs, 1H), 3.12 (dd, J=7.0, 12.2 Hz, 1H),2.74 (t, J=8.7 Hz, 1H), 2.7-2.58 (m, 1H), 2.50 (s, 3H), 2.36 (s, 3H),2.28 (s, 4H), 1.50-1.25 (m, 6H), 1.20-0.80 (4H).

EXAMPLE 13

[0207] Rat Jejuvanal Test

[0208] The rat intestine perfusion technique is a direct way to measurethe regional absorption properties of a test compound in thegastrointestinal tract. Rat intestinal permeability coefficient (Peff)can be used to predict human in vivo oral absorption of passivelyabsorbed compounds. Fagerholm, M. Johansson, and H. Lennernäs,“Comparison between permeability coefficients in rat and human jejunum”,Pharm. Res., 13, 1996, 1336-1342, have demonstrated a good correlationbetween rat Peff and human fraction of dose absorbed (Fa) for a seriesof compounds. Meanwhile, some other characteristics such as formulableMaximum Absorbable Dose (MAD), FDA Biopharmaceutical Classification,etc. can also be estimated.

[0209] Materials

[0210] Perfusion buffer (PB) consisted of KC1 (5.4 mM), NaC1(48 mM),Na₂HPO₄ (28 mM), NaH₂PO₄ (43 mM), mannitol (35 mM), polyethylene glycol(PEG)-4000 (0.1%, w/v), glucose (10 mM). The pH was adjusted to 6.8 withNaOH and osmolarity was adjusted to 290+10 mOsm/l with 1.0 M NaC1.Before the experiment, ¹⁴C-PEC-4000 (0.02 μCi/mL), 3H-mannitol (0.025μCi/mL), metoprolol (20 μg/mL), and ODV succinate or fumarate (50 μg/mL)were added.

[0211] Rats used in this study were Charles River CD males, ranging inweight from approximately 300-350 grams.

[0212] Internal Standard Compounds

[0213] Metoprolol (a well-absorbed and passively transported compound)was used as a standard and tested simultaneously along with the ODVcompounds. Glucose (a well-absorbed and actively transported compound)was used to monitor the physiological functionality of the intestinalbarriers. ¹⁴C-labeled PEG-4000 was used as a non-absorbable marker todescribe the water flux across the intestinal wall. ³H-labeled mannitolwas used as a paracellularly transported marker to indicate theintegrity of the intestinal tight junctions.

[0214] Analytical Methods

[0215] All chemicals were of analytical grade. After each experiment,all the analytic assays were performed promptly. For isotopedeterminations, 0.5 mL of perfusate sample containing ¹⁴C PEG-4000 and³H-mannitol was mixed with 5 mL of scintillation cocktail. Radioactivitywas counted in a liquid scintillation counter (Wallac 1409). Glucoseconcentration was determined by the glucose oxidase method (BiochemistryAnalyzer). Metoprolol and the ODV compounds were analyzed by HPLC-UV/Vis(HP-1100 with a diode-array detector), using a YMC AQ 120μ, 5μ, 150×4.6mm column and step gradient mobile phase containing water/0.1% TFA andacetonitrile. The ODV compounds and metoroplol were detected at 226 and272 nm UV wavelength, respectively. Blank perfusate was assayed toevaluate the interference at these chromatographic conditions.

[0216] In situ Rat Jejunal Perfusion

[0217] The perfusions were performed in three intestinal sections ofanesthetized rats: duodenum-jejunum, ileum, and colon. The lengths ofthe segments were approximately 10-12 cm for small intestine segmentsand 5-6 cm for colon segments. An inflow cannula was inserted at theproximal end and an outflow cannula was inserted at the distal end.Perfusate was pumped through the segment at 0.19 mL/min, and collectedat 20, 40, 55, 70, 85 and 100 minutes.

[0218] ODV succinate or fumarate was added to the perfusion workingbuffer at a concentration of 50 μg/mL, which is approximately equivalentto a 200 mg human does. The disappearance rates of ODV compound,metoprolol, and glucose were determined from each collection interval bycomparing to the initial compound solution remaining in the syringe atthe end of the 100 minutes. This is to correct for any losses due tobinding to the syringe or tubing. Meanwhile, drug concentration inperfusate samples were corrected for water influx/efflux, which wascomputed, based on ¹⁴C-PEG-4000 concentration changes.

[0219] Data Analysis

[0220] a. Recovery and Water Flux

[0221] Recovery of ¹⁴C-PEG-4000 was determined to provide information onthe integrity of the perfused intestinal segment:

% PEG_(rec)=(ΣPEG_(out)/ΣPEG_(in))*100

[0222] Overall ¹⁴C-PEG-4000 recovery was calculated and any data forwhich the individual recovery fell outside of the range of 96%-103% wasexcluded from the data set. Values below this range would indicatetissue damage that allows passage of PEG-4000 outside of the perfusedsegment, while values above this range would indicate significant watermovement out of the segment.

[0223] Water movement across the gut wall was determined by calculationof net water fluid:

Net Water Flux (NWF)=[(1−PEG_(out)/PEG_(in))*Q]/L

[0224] where PEG_(out) and PEG_(in) are the amount of radioactivity(dpm) of ¹⁴C-PEG-4000 in inlet and outlet sides of the perfusedintestinal segment, respectively; Q is the flow rate of perfusate; and Lis the length of perfused segment (cm).

[0225] b. Peff Calculation

[0226] The presence of the ODV compound in the perfusate was determinedby HPLC. The amount of drug present at each time point was corrected forwater movement across the wall of the intestine:

C _(out,corr) =C _(out)*(PEG_(in)/PEG_(out))

[0227] where C_(out) is the concentration of drug in outlet perfusate;C_(out,corr) is the concentration of drug in outlet perfusate correctedfor water moving in or out of the segment, as determined by the recoveryof ¹⁴C-PEG-4000.

[0228] Effective intestinal permeability, Peff (cm/sec), was determinedby the following equation:

Peff=[Q*(C _(in) −C _(out,corr))/C _(in)]/2 μrL

[0229] where Q is the flow rate; C_(in) is the concentration of drug ininlet perfusate; 2 μrL is the inner surface area of the perfusedsegment, with r assumed to be 0.18 cm in the rat (see G. Amidon, H.Lennernäs, V. Shah, J. Crison. “A theoretical basis for abiopharmaceutic drug classification: The correlation of in vitro drugproduct dissolution and in vivo bioavailability.” Pharm. Res. 12, 1995,413-420) and L the length of the perfused segment (cm).

[0230] c. Fraction Absorbed (Fa)

[0231] The fraction of dose absorbed, Fa, in human is currentlypredicted from (Fagerholm, M. ibid:

Fa=100*(1−e ^(−(2*(α*Peff,rat+β)*(tres/r)))

[0232] where α and β are the correction factors, tres is the residencetime in human small intestine; and r is the radius of the human smallintestine.

[0233] d. Maximum Absorbable Dose (MAD)

[0234] The maximum absorbable dose, MAD, in humans can be calculated as:$\begin{matrix}{{MAD} = \quad {{ka}*{\int_{0}^{t}{{Cs}*V*\quad {t}}}}} \\{{MAD} = \quad {{ka}*{Cs}*V_{0}*{tres}}} \\{= \quad {\left( {{2*{Peff}},{h\text{/}r}} \right)*{Cs}*V_{0}*{tres}}}\end{matrix}$

[0235] where ka is a first-order absorption rate constant; tres is theresidence time in a human small intestine; r is the radius of the humansmall intestine, and V_(o) is the estimated volume of fluid present inthe gastrointestinal tract. See Johnson, K. C., Swindell, A. C.“Guidance in setting of drug particle size specifications to minimizevariability in absorption”. Pharm. Res. 13(2), 1996, 1795-1798).

[0236] Results

[0237] Stability in Jejunal Fluids

[0238] The stability of ODV succinate or fumarate in the solutions ofblank perfusion buffer (Pβ), and jejunal fluids (perfusion buffercollected by washing the isolated jejunal segment, pH=6.8) wasdetermined at 37° C. for up to 6 hours. The results indicated than noapparent degradation/metabolism of these two salt forms was evidentunder these test conditions. The results for ODV Succinate are presentedin Table 7 below. Similar data was obtained for ODV fumarate. TABLE 7Incubation Time Blank Perfusion Buffer¹ Intestinal fluid^(1,2) (hours)(ODV Succinate) (ODV Succinate) 0 100.0 100.0 2 99.9 99.6 3 100.3 99.8 699.9 100.1

[0239] Rat Jejunal Perfusion Results

[0240] Site-specific Absorption of ODV Succinate

[0241] The Peff values for ODV succinate in the small intestine(0.912±0.067×10-5 cm/sec in duodenum-jejunum, 1.73±0.22*10⁻⁵ cm/sec inileum) were lower than metoprolol's Peff values. The Peff value of ODVsuccinate in the colon was found to be 0.062±0.031×10⁻⁵ cm/sec, which isabout 10% of metoprolol's Peff value in the colon. The ileum segmentseems to be the best absorption site for ODV succinate. The Peff's ratioof duodenum-jejunum vs. ileum vs. colon was found to be 1.00:1.90:0.07,indicating that small intestinal sites of duodenum, jejunum, and ilcumpredominate the oral absorption of this compound (μ90%) for an IR dosageform. (Dongzhou Liu, S. Ng, R. Saunders, “Effect of Polysorbate 80 onTransport of Mannitol, Glucose, and Water Flux in Rat Small Intestine”,PharmSci., 2, 2000; Doungzhou Liu, S. Ng, R. Saunders. “InvestigatingIntestinal Uptake of Zaleplon in site and Simulating/Predicting OralAbsorption in vivo”, Submitted to PharmSci. 3(4), 2001).

[0242] Based on this experimental Peff, the human in vivo Fa of ODVsuccinate was predicted to be in the range of 60-77% in the smallintestine and a Fa of 20% in the colon, as shown in FIGS. 9 and 10 andTable 8 below. The delivery vehicle was perfusion buffer (pH=6.8). Thetest at each absorption site was repeated with 3 rats and the Peffvalues were averaged. TABLE 8 Rat Perfusion Data of ODV Succinate (50μg/ml) Absorption Site Peff_(ODV Succinate) (10⁻⁵ cm/sec)Peff_(Meloprolol) (10⁻⁵ cm/sec) Peff_(ODV Succinate)/Peff_(Meloprolol)Fa (%) (predicted human in vivo) Jejunum 0.912 ± 0.067 2.50 ± 0.11 0.37± 0.04 61.3 ± 2.5 lleum 1.73 ± 0.22 3.22 ± 0.07 0.54 ± 0.07 76.6 ± 3.8Colon 0.062 ± 0.031 0.583 ± 0.087 0.12 ± 0.07 16.4 ± 3.4

[0243] An estimated maximum absorbable dose (MAD) was generated based onthe rat data. The MAD of ODV succinate in the entire gastrointestinal(GI) tract (human) was estimated to be about 8.6 grams, which is the sumof 2236 mg in the duodenum-jejunum, 5629 mg in the ileum, and 683 mg inthe colon.

[0244] Site-specific Absorption of ODV Fumarate

[0245] The site-specific absorption of ODV fumarate was investigatedunder the same study conditions as ODV succinate (50 μg/ml in pH 6.8perfusion buffer). The test at each absorption site was repeated with 3rats (except for in the Jejunum, where only 2 rats were tested) and thePeff values were averaged. The results are shown in Table 9 below andFIGS. 11, 12, and 13. Rat Perfusion Data of ODV Fumarate (50 μg/ml)Absorption Site Peff_(ODV Fumarate) (10⁻⁵ cm/sec) Peff_(Meloprolol)(10⁻⁵ cm/sec) Peff_(ODV Fumarate)/Peff_(Meloprolol) Fa (%) (predictedhuman in vivo) Jejunum 0.245 ± 0.237 1.78 ± 0.93 0.09 ± 0.08 30.6 ± 20.0Ileum 0.678 ± 0.295 53 0.19 ± 0.06 44.7 ± 11.4 Colon 0 11 0 0

[0246] In general, the results show that ODV fumarate was less absorbedthan ODV succinate in the rat GI tract. In the small intestine, the Peffvalues of the fumarate salt (0.24-0.68×10⁻⁵ cm/sec) were only about 27μ40% of the succinate's Peff values. In the colon, no measurableabsorption of ODV furmarate was found.

[0247] The in vivo Fa of ODV fumarate was estimated to be in the rangeof 33-45% in the small intestine and 0 in the colon, indicating anoverall low absorption of this compound in the entire GI tract. The MADwas predicted to be about 440 mg.

[0248] The results of the site-specific intestinal absorption of ODVsuccinate and ODV fumarate show that ODV succinate has better absorptionin the small intestine and in the colon than ODV fumarate. Severalpublications have demonstrated that there is high correlation betweenthe rat perfusion model and in vivo human absorption (see e.g.,Doungzhou Liu, S. Ng, R. Saunders. “Investigating Intestinal Uptake ofZaleplon in site and Simulating/Predicting Oral Absorption in vivo”,Submitted to PharmSci. 3(4), 2001).

EXAMPLE 14

[0249] Bioavailability of O-desmethyl-venlafaxine in Beagle Dogs

[0250] Test Formulations

[0251] An intravenous solution containing 25 mg/mL of Form I of ODVsuccinate was prepared by mixing 3.8168 g (2.5% w/v) of the ODVsuccinate in a sufficient amount of water for injection, USP to obtain100 mL of solution.

[0252] An oral solution containing 25 mg/mL of Form I of ODV succinatewas prepared by mixing 3.8170 g (2.5% w/v) of the ODV succinate in asufficient amount of water for injection, USP to obtain 100 mL ofsolution. Prior to administration, the oral solution (25 mg/mL) wasdiluted to a concentration of 7.5 mg/mL with water.

[0253] Tablets each containing the ingredients listed in the table belowwere prepared by the method described in Example 15 for preparing ODVSuccinate Formulation #2. Ingredient mg per tablet % w/w ODV Succinate(Form I was used in the 116.70 39.2 preparation) (75.00 as free base)HPMC 2208 USP 100, 100 SR 175.05 58.8 Magnesium Stearate 5.95 2.0Purified Water USP q.s. q.s. Total 297.70 100.0

[0254] Capsules (HGC Size 0) each containing the ingredients listed inthe table below were prepared by the method described in Example 15 forpreparing ODV Succinate Formulation #1. Ingredient mg per tablet % w/wODV Succinate (Form I was used in the 116.70 39.5 preparation) (75.00 asfree base) Microcrystalline Cellulose (Avicel 177.26 60.0 PH200)*Magnesium Stearate 1.48 0.5 Total 295.44 100.0

[0255] Study Animals

[0256] Six male beagle dogs with body weights ranging between 10.2 and16.0 kg were used in this study. The dogs were housed and given freeaccess to water and food.

[0257] Study Design

[0258] The six dogs were dosed in a 4 period study. In Period 1, thedogs received 1 mL of the intravenous solution. In Period 2, the dogsreceived 10 mL of the oral solution. In Period 3, the dogs received thetablet. In Period 4, the dogs received the capsule. There was a one weekwash out period between the first two treatment periods and a one monthwash out period between treatment periods 2 and 3. Between periods 3 and4, there was a one week wash out period. For periods 1 and 2, all dogswere fasted overnight with free access to water and fed after thefour-hour bleeding. For periods 3 and 4, all dogs were fed 30 minutesprior to dosing and with free access to water.

[0259] Blood Samples

[0260] In periods 1 and 2, blood samples were drawn from the jugularvein at 0 (predose), 0.05 (intravenous only) and 0.13 (intravenousonly), 0.25, 0.5, 1, 1.5, 2, 3, 4, 8, 12, 24, 32, and 48 hours afterdosing into 5 mL heparinized vacutainers and immediately placed on ice.In periods 3 and 4, blood samples were drawn from the jugular vein at 0(predose), 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, and 32 hoursafter dosing into 5 mL heparinized vacuatiners and immediately placed onice. Plasma was separated in a refrigerated centrifuge and stored at−70° C. Plasma samples were then assayed.

[0261] Sample Analysis

[0262] Plasma O-desmethyl-venlafaxine concentrations were determined bythe HPLC method using mass spectrometric detection described in Hicks,D. R., Wolaniuk, D., Russel, A., Cavanaugh, N., Kraml, M., “Ahigh-performance liquid chromatographic method for the simultaneousdetermination of venlafaxine and O-desmethylvenlafaxine in biologicalfluids”, Ther. Drug Monit. 16:100-107 (1994), which is herebyincorporated by reference. Based on a 0.2 mL sample volume, the methodhas a limit of quantitation for O-desmethyl-venlafaxine of 5.05 ng/mL.Total O-desmethyl-venlafaxine levels were determined after incubating0.2 mL of plasma samples in β-glucuronidase for ˜18 hours.O-desmethyl-venlafaxine-glucuronide levels were determined bysubtracting the O-desmethyl-venlafaxine (separate extraction procedurewithout the use of β-glucuronidase and analyzed by HPLC-MS)concentrations from the total O-desmethyl-venlafaxine concentrations.

[0263] Data Analysis

[0264] Noncompartmental pharmacokinetic parameters were calculated fromthe individual dog plasma O-desmethyl-venlafaxine andO-desmethyl-venlafaxine-glucuronide concentration-time profiles. Areaunder the plasma concentration-time curves (AUC_(0−μ)) values werecalculated by the addition of AUC_(Last) (AUC_(Last)=the lineartrapezoid rule from time zero to the last measurable plasmaconcentration, CP_(Last)) and CP_(Last)/lambda. The values for lambdawere determined from the long-linear portion of the terminal slope ofthe plasma O-desmethyl-venlafaxine andO-desmethyl-venlafaxine-glucuronide concentration-time profile after theintravenous dose. The half-life (t_(half)) was calculated ast_(half)=0.693/lambda. The peak plasma concentration (C_(max)) and thetime to reach C_(max) (t_(max)) were noted directly from the plasmaconcentration-time profiles.

[0265] Absolute bioavailability was determined by comparing the dosenormalized AUC_(0−μ) values following the intravenous administration.

[0266] Results

[0267] All levels reported as below limit of quantitation (BLQ) wereassigned a value of zero for calculation purposes. The bioanalyticalresults demonstrated that O-desmethyl-venlafaxine-glucuronide levelsaccount for the major portion of total circulatingO-desmethyl-venlafaxine levels after the administration of ODVsuccinate.

[0268] Based on the total O-desmethyl-venlafaxine levels, the absorptionof O-desmethyl-venlafaxine and ODV succinate is essentially completefrom the oral formulation with 121%, 103% and 76% absolutebioavailability for the oral solution, capsule, and tablet formulations,respectively. Mean (% CV) Bioavailability Parameters of ODV Succinate(Expressed as Free ODV Levels) Oral Intravenous Solution Capsule TabletSolution (75 mg) (75 mg) (75 mg) (25 mg) AUC (ng*hr/mL)  835 (33)  904(29)  677 (23) 746 (14) C_(max) (ng/mL)  450 (23)  465 (37)  115 (24) —t_(max) (hr) 0.50 (55) 0.55 (68) 2.92 (35) — Absolute   37 (25)   40(17)   31 (24) — Bioavailability (%)

[0269] Mean (% CV) Bioavailability Parameters of ODV Succinate in BeagleDogs Expressed as ODV-glucuronide Levels Oral Intravenous SolutionCapsule Tablet Solution (75 mg) (75 mg) (75 mg) (25 mg) AUC 17349 (14)13381 (14) 11686 (18) 4814 (11) (ng*hr/mL) C_(max) (ng/mL)  3917 (33) 2633 (20)  1235 (15)  856 (20) t_(max) (hr)  2.50 (22)   1.67 (24)  3.67 (14)   2.33 (22)  Absolute  121 (13)   95 (9)    81 (11) —Bioavailability (%)

[0270] Mean (% CV) Bioavailability Parameters of ODV Succinate in BeagleDogs (n = 6) Expressed as Total ODV Levels Oral Intravenous SolutionCapsule Tablet Solution (75 mg) (75 mg) (75 mg) (25 mg) AUC 18184 (13)14285 (13) 12362 (18) 5560 (9) (ng*hr/mL) C_(max) (ng/mL)  4026 (32) 2841 (19)  1337 (15) N/A t_(max) (hr)   2.5 (22)   1.67 (24)   3.67(14)  N/A Absolute  109 (13)   86 (7)    74 (12) — Bioavailability (%)

EXAMPLE 15

[0271] 18 human subjects were given 75 mg each of Effexor® XR(venlafaxine formulation) (available from Wyeth-Ayerst Pharmaceuticalsof St. Davids, Pa.), ODV succinate formulation #1, and ODV succinateformulation #2 over three different periods.

[0272] ODV succinate formulation #1, which is a capsule, is shown in thetable below. ODV Succinate Formulation #1 Ingredient mg per tablet % w/wODV Succinate (Form I was used in the 113.9 33.5 preparation) (75.00 asfree base) Lactose Fast Flow 112.2 33.0 Microcrystalline Cellulose(Avicel PH200)* 112.2 33.0 Magnesium Stearate 1.7 0.5 Purified Waterq.s. q.s. Total 340.0 100.0

[0273] ODV succinate formulation #1 was prepared as follows. The ODVsuccinate was sieved through a 400 micron screen and dry mixed withlactose and microcrystalline cellulose in a high shear mixer. Theresulting mixture was wet granulated in a high shear mixer with purifiedwater and dried in an oven or fluid bed drier. The mixture was blendedwith magnesium stearate and encapsulated in a capsule (HGC Size 0).

[0274] ODV succinate formulation #2, which is a tablet, is shown in thetable below. ODV Succinate Formulation #2 Ingredient mg per tablet % w/wODV Succinate (Form I was used in the 113.81 37.94 preparation) (75.00as free base) HPMC 2208 USP 100, 100 SR 170.44 56.81 MicrocrystallineCellulose (Avicel PH200)* 7.50 2.50 Talc 6.75 2.25 Magnesium Stearate1.50 0.50 Purified Water q.s. q.s. Total 295.44 100.0

[0275] ODV succinate formulation #2 was prepared as follows. The ODVsuccinate was sieved through a 400 micron screen and dry mixed withHPMC, microcrystalline cellulose, and talc in a high sheer mixer. Themixture was then wet granulated with purified water and dried in an ovenor fluid bed drier. The resulting mixture was blended with HPMC andtalc. Magnesium stearate was added and the mixture was again blended.The mixture was then compressed into a tablet.

[0276] All doses were administered after subjects consumed astandardized medium-fat breakfast. Blood samples were taken 0.5, 1, 2,4, 6, 8, 12, 16, 20, 24, 28, 36, 48, and 72 hours after administration.The plasma concentrations of venlefaxine and O-desmethyl-venlafaxine ineach blood sample was determined by the method described in Hicks, D.R., Wolaniuk, D., Russel, A., Cavanaugh, N., Kraml, M., “Ahigh-performance liquid chromatographic method for the simultaneousdetermination of venlafaxine and O-desmethylvenlafaxine in biologicalfluids”, Ther. Drug Monit. 16:100-107 (1994), which is herebyincorporated by reference.

[0277] The results are shown in the table below. Plasma Concentrationsof Venlafaxine* C_(max) AUC Formulation (ng/mL) t_(max) (hr) t_(1/2)(hr) (ng*hr/mL) Effexor ® XR Mean ± Stand. Dev. 40 ± 16 5.9 ± 0.5 9.5 ±2.4 628 ± 265 % CV 39.9% 8.0% 25.6% 42.2% Min-Max 11-77 4-6 4.8-13.8139-1292

[0278] Plasma Concentrations of O-desmethylvenlafaxine C_(max) AUCFormulation (ng/mL) t_(max) (hr) t_(1/2) (hr) (ng*hr/mL) Effexor ® XRMean ± Stand. Dev. 88 ± 25 9.3 ± 2.9 13.2 ± 4.0  2430 ± 647 % CV 28.9%31.2% 30.4% 26.6% Min-Max  37-142 6-16 7.6-24.8 1582-3835 ODV SuccinateFormulation #1 Mean ± Stand. Dev. 282 ± 57  3.1 ± 1.3 9.4 ± 1.4 3491 ±814 % CV 20.1% 43.0% 14.7% 23.3% Min-Max 173-399 0.5-6   6.8-11.51667-5086 ODV Succinate Formulation #2 Mean ± Stand. Dev. 135 ± 54  7.3± 5.5 9.3 ± 1.9 3185 ± 944 % CV 39.9% 75.4% 20.5% 29.6% Min-Max  65-2792-28 6.1-13.7 1100-4767

[0279] The table below shows the number of human subjects whoexperienced various adverse effects after administration of a singleddose of ODV Succinate Formulations #1 and 2.

[0280] Without being bound to any particular theory, it is believed thatadverse effects observed with Formulation #1 are related to the peakblood plasma level and/or tmax of the formulation. By flattening thecurve as in sustained release formulation, Formulation #2, the peakblood plasma level is reduced and the tmax delayed. Thus, in patients,as a flattened blood plasma concentration to time profile is achievedadverse event are reduced or eliminated. Thus, a pharmaceuticalcomposition comprising a sustained release formulation of ODV succinatehaving a peak blood plasma profile of less than about 225 ng/ml willhave reduced side effects such as nausea and emesis. Adverse EffectsAfter Administration of a Single Dose of ODV Succinate Formulations #1and 2 ODV Succinate ODV Succinate Formulation #1 Formulation #2 AdverseEffect (n = 18) (n = 18) Nauseau (VAS > 5 mm) 10  1 Nauseau (VAS > 20 mm6 1 or spontaneous) Vomiting 2 — Diarrhea 1 — Abdominal Pain — —Headache 2 — Vaso-vagal Malaise 2 — Trismus 1 —

[0281] The present invention is not to be limited in scope by thespecific embodiments described herein. Indeed, various modifications ofthe invention in addition to those described herein will become apparentto those skilled in the art from the foregoing description and theaccompanying figures. Such modifications are intended to fall within thescope of the appended claims.

[0282] It is further to be understood that values are approximate, andare provided for description.

[0283] Patents, patent applications, publications, procedures, and thelike are cited throughout this application, the disclosures of which areincorporated herein by reference in their entireties. To the extent thata conflict may exist between the specification and a reference, thelanguage of the disclosure made herein controls.

What is claimed:
 1. A compound which is O-desmethyl venlafaxinesuccinate.
 2. The compound of claim 1, wherein the compound is a hydrateof O-desmethyl venlafaxine succinate.
 3. The compound of claim 2 whichis O-desmethyl venlafaxine succinate monohydrate.
 4. The compound ofclaim 1 wherein the salt is crystalline.
 5. The compound of claim 4wherein the compound exhibits an X-ray powder diffraction pattern havingcharacteristic peaks expressed in degrees 2θ (±0.2° 2θ) at 10.20, 14.91,20.56, 22.13, 23.71, 24.60, and 25.79.
 6. The compound of claim 4 havingan endotherm at about 131° C.
 7. The compound of claim 4 having an X-raypowder diffraction pattern substantially the same as that shown inFIG.
 1. 8. The compound of claim 4 wherein the compound exhibits anX-ray powder diffraction pattern having characteristic peaks expressedin degrees 2θ (±0.2° 2θ) at 13.18, 14.04, 14.35, 14.66, 16.68, 17.67,19.24, 25.13, and 31.78.
 9. The compound of claim 8 wherein the compoundexhibits an X-ray powder diffraction pattern having characteristic peaksexpressed in degrees 2θ (±0.2° 2θ) at 10.25, 13.18, 14.04, 14.35, 14.66,16.68, 17.67, 19.24, 20.38, 20.56, 23.41, 23.78, 24.57, 25.13, 25.80,and 31.78.
 10. The compound of claim 4 having an endotherm at about 127°C.
 11. The compound of claim 4 having an X-ray powder diffractionpattern substantially the same as that shown in FIG.
 2. 12. The compoundof claim 4 wherein the compound exhibits an X-ray powder diffractionpattern having characteristic peaks expressed in degrees 2θ (±0.2° 2θ)at 13.74, 22.55, and 32.42.
 13. The compound of claim 12 wherein thecompound exhibits an X-ray powder diffraction pattern havingcharacteristic peaks expressed in degrees 2θ (±0.2° 2θ) at 10.36, 13.74,14.40, 14.68, 14.96, 16.75, 17.48, 17.76, 19.26, 20.42, 20.74, 22.55,23.58, 23.82, 24.92, 26.00, 31.86, and 32.42.
 14. The compound of claim4 having an X-ray powder diffraction pattern substantially the same asthat shown in FIG.
 3. 15. The compound of claim 4, wherein the compoundexhibits an X-ray powder diffraction pattern having characteristic peaksexpressed in degrees 2θ (±0.2° 2θ) at 11.29, 17.22, 19.64, 20.91, 21.61,28.86, 29.80, 30.60, 36.85, and 37.70.
 16. The compound of claim 15,wherein the compound exhibits an X-ray powder diffraction pattern havingcharacteristic peaks expressed in degrees 2θ (±0.2° 2θ) at 10.46, 11.29,13.69, 14.48, 15.17, 16.62, 17.22, 17.61, 19.22, 19.64, 20.91, 21.61,22.55, 23.84, 24.77, 25.34, 25.92, 26.40, 28.86, 29.80, 30.60, 33.17,36.85, and 37.70.
 17. The compound of claim 4 having an endotherm at145° C.
 18. The compound of claim 4 having an X-ray powder diffractionpattern substantially the same as that shown in FIG.
 4. 19. The compoundof claim 1 wherein the compound is amorphous.
 20. The compound of claim19 having a T_(g) onset at 18° C.
 21. The compound of claim 1 having anX-ray powder diffraction pattern substantially the same as that shown inFIG.
 5. 22. The compound of claim 1 having a solubility in water of atleast 30 mg/ml at about 25° C.
 23. A pharmaceutical compositioncomprising O-desmethyl venlafaxine succinate and a pharmaceuticallyacceptable carrier or excipient.
 24. The pharmaceutical composition ofclaim 23 further comprising venlafaxine.
 25. A pharmaceutical dosageform comprising a therapeutically effective amount of O-desmethylvenlafaxine succinate and a pharmaceutically acceptable carrier orexcipient.
 26. An oral dosage form comprising a therapeuticallyeffective amount of O-desmethyl venlafaxine succinate and apharmaceutically acceptable carrier or excipient.
 27. The oral dosageform of claim 26, wherein the dosage form is a tablet or capsule. 28.The oral dosage form of claim 26, wherein the oral dosage form is asustained release formulation.
 29. The oral dosage form of claim 26,further comprising a rate controlling polymer material.
 30. The oraldosage form of claim 29, wherein the rate controlling polymer materialis selected from hydroxyalkyl celluloses, poly(ethylene) oxides, alkylcelluloses, carboxymethyl celluloses, hydrophilic cellulose derivatives,and polyethylene glycol.
 31. The oral dosage form of claim 29, whereinthe oral dosage form comprises from about 30 to about 50% by weight ofO-desmethyl-venlafaxine succinate and from about 40 to about 70% byweight of the rate controlling polymer material, based upon 100% totalweight of oral dosage form.
 32. The oral dosage form of claim 31,wherein the oral dosage form comprises from about 32 to about 44% byweight of O-desmethyl-venlafaxine succinate and from about 45 to about66% by weight of the rate controlling polymer material, based upon 100%total weight of oral dosage form.
 33. The oral dosage form of claim 26,wherein the oral dosage form further comprises a binder.
 34. The oraldosage form of claim 33, wherein the binder is microcrystallinecellulose.
 35. A method of treating a patient suffering from depressioncomprising providing to a patient in need thereof an effective amount ofO-desmethylvenlafaxine succinate.
 36. A method of treating a patientsuffering from anxiety comprising providing to a patient in need thereofan effective amount of O-desmethylvenlafaxine succinate.
 37. A method oftreating a patient suffering from panic disorder comprising providing toa patient in need thereof an effective amount of O-desmethylvenlafaxinesuccinate.
 38. A method of treating a patient suffering from generalizedanxiety disorder comprising providing to a patient in need thereof aneffective amount of O-desmethylvenlafaxine succinate.
 39. A method oftreating a patient suffering from post traumatic stress disordercomprising providing to a patient in need thereof an effective amount ofO-desmethylvenlafaxine succinate.
 40. A method of treating a patientsuffering from premenstrual dysphoric disorder comprising providing to apatient in need thereof an effective amount of O-desmethylvenlafaxinesuccinate.
 41. A method of treating a patient suffering from a conditionselected from fibromyalgia, agorophobia, attention deficit disorder,obsessive compulsory disorder, social anxiety disorder, autism,schizophrenia, obesity, anorexia nervosa, bulimia nervosa, Gilles de laTourette Syndrome, vasomotor flushing, cocaine and alcohol addiction,sexual dysfunction, borderline personality disorder, chronic fatiguesyndrome, urinary incontinence, pain, Shy Drager syndrome, Raynaud'ssyndrome, Parkinson's disease, and epilepsy comprising providing to apatient in need thereof an effective amount of O-desmethylvenlafaxinesuccinate.
 42. A method of enhancing cognition or treating cognitiveimpairment in a patient comprising providing to a patient in needthereof an effective amount of O-desmethyl-venlafaxine succinate.
 43. Amethod for cessation of smoking or other tobacco uses in a patientcomprising providing to a patient in need thereof an effective amount ofO-desmethyl-venlafaxine succinate.
 44. A method for treatinghypothalamic amenorrhea in a depressed or non-depressed human femalecomprising providing to a human female in need thereof an effectiveamount of O-desmethyl-venlafaxine succinate.
 45. A method of loweringthe incidence of nausea, vomiting, diarrhea, abdominal pain, headache,vaso-vagal malaise, or trismus resulting from the oral administration ofO-desmethylvenlafaxine succinate to a patient comprising orallyadministering to a patient in need thereof a therapeutically effectiveamount of a sustained release formulation of O-desmethyl-venlafaxinesuccinate having a blood plasma level of no more than about 225 ng/ml.46. A method of preparing O-desmethyl-venlafaxine comprising the step ofdemethylating venlafaxine or a salt thereof with an alkali metal salt ofa trialkyl borohydride.
 47. The method of claim 46, wherein each alkylgroup in the trialkyl borohydride is independently a C₁-C₆ alkyl. 48.The method of claim 47, wherein the alkali metal salt of a trialkylborohydride is selected from L-selectride, K-selectride, lithiumtriethylborohydride, potassium triethylborohydride, and mixturesthereof.
 49. The method of claim 48, wherein the alkali metal salt of atrialkyl borohydride is L-selectride.
 50. The method of claim 46,wherein the demethylation step is performed at a temperature of fromabout 60 to about 140° C.
 51. The method of claim 46, further comprisingthe step of converting the O-desmethyl-venlafaxine toO-desmethyl-venlafaxine succinate.
 52. The method of claim 46, furthercomprising the step of deactivating any boron containing byproductsproduced by the demethylation reaction.
 53. The method of claim 52,wherein the deactivating step comprises oxidizing the boron containingbyproducts.
 54. The method of claim 53, wherein the oxidizing stepcomprises reacting the boron containing byproducts with an oxidizingagent selected from hydrogen peroxide, sodium perborate, and mixturesthereof.
 55. The method of claim 53, wherein the oxidizing stepcomprises adding the boron containing byproducts to an oxidizing agentor a solution comprising an oxidizing agent.
 56. A method of preparingO-desmethyl-venlafaxine comprising the steps of: (a) demethylatingvenlafaxine or a salt thereof with an alkali metal salt of a trialkylborohydride to yield an alkali metal salt of O-desmethyl-venlafaxine;and (b) converting the alkali metal salt of-O-desmethyl-venlafaxine tothe free base of O-desmethyl-venlafaxine.
 57. The method of claim 56,wherein step (b) comprises neutralizing the alkali metal salt ofO-desmethyl-venlafaxine with acid.
 58. The method of claim 56, furthercomprising the step of (c) converting the free base ofO-desmethyl-venlafaxine to O-desmethyl-venlafaxine succinate.
 59. Themethod of claim 56, wherein the venlafaxine in step (a) is the free baseof venlafaxine.
 60. A sustained release formulation comprisingO-desmethyl-venlafaxine succinate and a pharmaceutically acceptablecarrier or excipient, wherein the sustained release formulation providespeak serum levels of up to about 225 ng/ml.